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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Single dose, 14-day post-exposure observation period
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study conducted to be in compliance with EPA/TSCA Health Effects Testing Guidelines, 40 CFR Part 798/1175 (EPA OTS 798.1175); some deviations noted in "Overall Remarks" section but not sufficient to impact validity of study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OTS 798.1175 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
: Minor deviations from the guideline occurred. There was no information provided on test material purity or actual temperature and humidity in the testing area. These deviations were not sufficient to impact the validity of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): tert-butyl acetate
- Appearance: clear, colorless liquid
- Received at testing laboratory: 7/14/97
- Source of test material: Arco Chemical Company (now LyondellBasell Industries)
- Specific gravity of test material: 0.85
- Storage condition of test material: room temperature and humidity
- Purity of test material: not reported, test material used as received

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS:
-Source: Ace Animals, Boyertown, PA (received on 6/24, 7/1, and 7/8/97)
-Animals: 5/sex/dose group
-Age: young adults (born weeks of 4/22 through 5/27/97)
-Quarantine period: at least one week
-Weight at Study Initiation: males were 265 - 296 g and females were 201 - 280 g
-Housing: 5/sex/cage in suspended wire cages
-Bedding: placed beneath the cages and changed at least 3x/week
-Diet: Purina® Rat Chow® Diet # 5012 ad libitum except for 16 - 20 hours prior to dosing
-Water: ad libitum
-Identification method: cage notation and indelible body marks
-Method of Animal Distribution: randomly assigned to treatment groups

ENVIRONMENTAL CONDITIONS:
-Room temperature: controlled; values not specified
-Humidity: not reported
-Light: 12 hour light/dark cycle

IN-LIFE DATES:
-Date of start of experiment (first exposure): 7/18/97
-Date of experiment termination (last data collected): 8/1/97

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test material was administered as received. The dose volume was based on the test sample weight as calculated from the specific gravity (0.85). Rats were fasted for 16-20 hours prior to dosing. A single dose was administered orally by syringe and dosing needle.
Doses:
Initially, one group of rats received a dose of 5000 mg/kg bw, orally by gavage. Since test substance-related deaths occurred at this dose level, two additional groups of rats, administered either a dose of 2000 or 7000 mg/kg bw, were added to the study.
No. of animals per sex per dose:
5 rats/sex/dose group
Control animals:
no
Details on study design:
OBSERVATION PERIOD: 14 days

CAGE SIDE OBSERVATIONS: All animals were observed twice daily for mortality and moribundity.

DETAILED CLINICAL OBSERVATIONS: Observations were performed 1, 2 and 4 hours post-dose, then daily for 14 days.

INDIVIDUAL BODY WEIGHTS: Recorded pre-test, then weekly; also recorded at death and at termination in survivors.

SACRIFICE AND PATHOLOGY: A necropsy was performed on all animals that died on study. Surviving animals were sacrificed at conclusion of the observation period and also subjected to a necropsy. A gross pathology exam was performed on all animals. Abnormal tissues were preserved in 10% buffered formalin for possible future microscopic examination.
Statistics:
Means and standard deviations were calculated for body weights. The LD50 value and 95% confidence limits of the mortality data were calculated by the method of Litchfield and Wilcoxon (1949).

Reference:
Litchfield JT Jr. and Wilcoxon F, 1949. A Simplified Method of Evaluating Dose-Effect Experiments. JPET 96:99-113.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
4 100 mg/kg bw
95% CL:
3 185 - 5 277
Sex:
female
Dose descriptor:
LD50
Effect level:
4 750 mg/kg bw
95% CL:
3 848 - 5 864
Sex:
male/female
Dose descriptor:
LD50
Effect level:
4 500 mg/kg bw
95% CL:
3 783 - 5 353
Mortality:
At the 7000 mg/kg bw dose level, all rats were found dead on the day of (3 males and 5 females) or the day following dosing (2 males). For the 5000 mg/kg bw dose group, mortality occurred in 1 rat of each sex on the day of dosing and 3 males and 1 female on the day following dosing. There was no mortality among rats that received the lowest dose of 2000 mg/kg bw.
Clinical signs:
Abnormal clinical signs recorded in rats prior to death included lethargy, ataxia, piloerection, flaccid muscle tone, dyspnea, loss of righting reflex, prostration, tremors, and coma. For surviving animals of both sexes of the 2000 and 5000 mg/kg groups, abnormal clinical signs observed included lethargy, ataxia, flaccid muscle tone, prostration, and piloerection. A single low-dose group male appeared clinically normal throughout the study. In addition, a single incidence of bloated abdomen (1 male in the 5000 mg/kg bw group) and chromorhinorrhea (1 male in the 2000 mg/kg bw group) were also noted for survivor animals. By Day 2 of the study, all surviving animals appeared clinically normal.
Body weight:
All surviving animals gained weight normally over the 14-day observation period.
Gross pathology:
Necropsy of animals that died on study revealed abnormalities of the lungs (red areas and/or darker than normal); spleen (pale); kidneys (pale areas); liver (pale areas and/or darker than normal); and gastrointestinal tract (red; red areas; pale; distension with fluid, gas and/or mucus); as well as wetness and staining (red and brown) of the nose/mouth area. No gross abnormalities were noted for animals surviving to termination of the study.

Applicant's summary and conclusion

Interpretation of results:
other: Not classified (NC) for Directive 67/548/EEC or EU CLP Regulation (EC) No. 1272/2008 for acute lethality; classified Category V per UN GHS. NC for Directive 67/548/EEC for STOT-SE; classified Category 3 for EU CLP Regulation (EC) No. 1272/2008 and UN GHS.
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
In an acute oral toxicity test, the oral LD50 was 4100 mg/kg bw for male rats, 4750 mg/kg bw for female rats, and 4500 mg/kg bw for both sexes combined when administered a single dose of tertiary butyl acetate. Abnormal clinical signs were recorded in rats prior to death and were limited in surviving animals to the first twenty-four hours after dosing. Signs were generally dose dependent and occurred more frequently in the higher dose groups. Clinical signs in survivors indicating reversible effects on the central nervous system included lethargy, ataxia, flaccid muscle tone, prostration, and piloerection. All survivors gained weight and were clinically normal by Day 2 of the study.

In accordance with Directive 67/548/EEC, tertiary butyl acetate is not classified for acute oral toxicity. Based on an acute oral LD50 value of 4500 mg/kg bw for male and female rats, tertiary butyl acetate is classified as Category V for acute lethality by the oral route according to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS); however, there is no Category V in EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Therefore, tertiary butyl acetate is not classified for acute lethality by the oral route according to EU CLP GHS in this study. Based on clinical signs indicating reversible effects on the central nervous system, tertiary butyl acetate is classified as Category 3 for classification and labeling under UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 for Specific Target Organ Toxicity – Single Exposure (STOT-SE). A harmonized classification exists for tertiary butyl acetate; however, this hazard category is not included. A recommendation is made to add STOT-SE Category 3 H336-May cause drowsiness or dizziness to Table 3.1 of Annex VI.
Executive summary:

In an acute oral toxicity study, three groups containing five rats/sex/group were administered a single dose of tertiary butyl acetate by oral gavage at dose levels of 2000, 5000 or 7000 mg/kg bw. The animals were observed for mortality and adverse clinical signs for a period of 14 days. Deaths occurred in 4 of 5 males and 2 of 5 females at the 5000 mg/kg bw dose level. All animals receiving 7000 mg/kg bw died by the day after dosing. Clinical signs indicative of central nervous system depression were observed at all dose levels. Organs discolored pale or dark red and distention of the gastrointestinal tract were observed at necropsy for the animals that died prior to study termination. There were no adverse effects on body weight or gross abnormalities in animals surviving to termination. Under the conditions of this study, the oral LD50 of tertiary butyl acetate in Wistar albino rats was 4100 mg/kg bw for male rats, 4750 mg/kg bw for female rats, and 4500 mg/kg bw for both sexes combined.