Isobutyl acetate

Endpoint summary

Description of key information

The oral LD50 of isobutyl acetate was determined to be 13413 mg/kg bw in male rats (Smyth, 1962).
The inhalation LC50 of isobutyl acetate is assessed to be approximately 30 mg/L in rats (Smyth, 1962 and supporing studies).
The dermal LD50 of isobutyl acetate was determined to be > 17,400 mg/kg in male rabbits (Smyth, 1962).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study is in accordance with OECD TG 401; restriction: poor information on test substance

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

no fasted animals, limited reporting

GLP compliance:

no

Remarks:

pre-GLP study

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Carworth-Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: own breeding
- Age at study initiation: 4 to 5 weeks
- Weight at study initiation: 90 to 120 g
- Fasting period before study: no
- Housing: no data
- Diet (e.g. ad libitum): Rockland rat diet, complete

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: gavage

Vehicle:

not specified

Doses:

Dosages are arranged in a logarithnic series differing by a factor of two.
no data on individual doses.

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no data
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: no data

Statistics:

LD50 values were calculated by the method of Thompson (Thompson WR (1947), Bacteriol Rev 11: 115) using the Tables of Weil (Weil GS (1952), Biometrics 8: 249) . The figures in parentheses show the limits of +/- 1.96 standard deviations.

Sex:

male

Dose descriptor:

LD50

Effect level:

13 413 mg/kg bw

Remarks on result:

other: 10888-16636 mg/kg bw (+/- 1.96 standard deviations)

The acute oral LD50 was reported as 15.4 (12.5 - 19.1) mL/kg bw. The figures in parentheses show the limits of +/- 1.96 standard deviations. Using a density of 0.871 g/mL (Sect. 4.4), the LD50 calculates to 13413 mg/kg bw.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral LD50 was 13413 mg/kg bw in male rats. No classifcation required according to EU legislation.

Executive summary:

The acute oral toxicity of isobutyl acetate was determined in groups of 5 male Carworth-Wistar rats receiving the test material by oral gavage. The dosages were spaced by a factor of 2 (logarithmically). The observation period was 14 days. The LD50 and a range of +/- 1.96 SD was calculated according to the method of Thomson (1947). Overall the study was conducted in accordance with the recently replaced OECD test guideline 401.

The acute oral LD50 was 13413 mg/kg bw in rats (Smyth et al., 1962).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

13 413 mg/kg bw

Quality of whole database:

Only one reliable study, which is supported by another study of lower reliability (Klimisch score 3).

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

30 000 mg/m³ air

Quality of whole database:

One acute inhalation study with isobutyl acetate (Klimisch score 3) and two studies for n-butyl acetate (read-across from supporting substance (structural analogue or surrogate), Klimisch score 2) are available. No definite study can be chosen and the endpoint is assessed in a Weight-of-evidence approach. The quality of the database is high.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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 (only 4 animals per group, occlusive wrapping, limited reporting)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

: only 4 animals per group, occlusive wrapping, limited reporting

Principles of method if other than guideline:

Pre-guideline test, but method similar to OECD TG 402

GLP compliance:

no

Remarks:

pre-GLP study

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.5 - 3.5 kg

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: part of the trunk
- % coverage: no data
- Type of wrap if used: impervious plastic film
- Restraining of animals: animals are immobilized during the 24 h exposure period

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): graduate doses were applied, but individual doses are not specified

Duration of exposure:

24 hours

Doses:

no individual doses specified

No. of animals per sex per dose:

4

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: no data
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: no data

Statistics:

LD50 values were calculated by the method of Thompson (1947, Bacteriol. Rev. 11, 115) using the tables of Weil (1952, Biometrics 8, 249. The limits of ± 1.96 standard deviations are presented.

Sex:

male

Dose descriptor:

LD50

Effect level:

> 17 400 mg/kg bw

Remarks on result:

other: The reported value is > 20 mL/kg bw. This is the highest dose which could technically be administered

Mortality:

no data

The acute dermal LD50 is reported as > 20 mL/kg bw. Using a density of 0.871 g/mL (Sect. 4.4), the LD50 calculates to > 17400 mg/kg bw.

 

There is no information on local effects reported.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal LD50 for isobutyl acetate was determined to be > 17400 mg/kg bw in male rabbits.

Executive summary:

The acute dermal toxicity of isobutyl acetate was determined in groups of 4 male albino New Zealand rabbits receiving graduate single doses of test substance per group. Number and quantity of individual doses are not specified. The exposure time was 24 hours followed by an observation period of 14 days. From mortality data, the LD50 and a range of ± 1.96 SD was calculated according to the method of Thomson (1947).

Overall, the study was conducted similar to OECD test guideline 402 with some restrictions (only 4 animals per group, occlusive wrapping, limited reporting).

The acute dermal LD50 for isobutyl acetate was > 17400 mg/kg bw (calculated from reported value of > 20 mL/kg bw and using a density of 0.871 mg/mL) in rabbits (Smyth, 1962).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

17 400 mg/kg bw

Quality of whole database:

Only one reliable study, which is supported by another study of lower reliability (Klimisch score 4, secondary source).

Additional information

Acute toxicity: oral

 

For the assessment of the acute oral toxicity of isobutyl acetate, only one valid study is available (Smyth, 1962, RL2, pre-GLP study, similar to OCED 401). In the acute oral toxicity study of Munch (1972, RL3), test animals (rabbits) were only observed for 24 hours after administration of test substance.

 

Smyth (1962)

The acute oral toxicity of isobutyl acetate was determined in groups of 5 male Carworth-Wistar rats receiving the test substance orally by gavage. The observation period was 14 days. Overall, the study was conducted in accordance with the recently retracted OECD test guideline 401.

The acute oral LD50 was 13413 mg/kg bw in rats (Smyth et al., 1962; RL2).

 

In the less reliable study (methdological and documentational deficiencies) an oral LD50 value of 4763 mg/kw bw in rabbits was determined (Only 24 hours observation period, Munch, 1972, RL3).

Acute toxicity: inhalation

 

To assess the acute inhalation toxicity potential of isobutyl acetate a weight of evidence approach is used. An acute inhalation toxicity study was conducted by Smyth, Carpenter, Weil (Smyth, 1962, pre-GLP study, RL3) which shows some deviations from current test guidelines. From this study, a LC50 of 30 mg/L can be derived.

 

This value is confirmed by supporting data obtained for the closely related substance n-butyl acetate (OPP/CMA, 1994, RL2 and BASF, 1988, RL2). In acute inhalation toxicity studies, no mortality was observed at the highest dose tested (30.2 mg/L in OPP/CMA 1994, 23.4 mg/L in BASF 1988) demonstrating that the LC50 is clearly above these concentrations.

 

Isobutyl acetate and n-butyl acetate are close related structural isomers only differing in the position of the terminal methyl groups in the butyl alcohol part of the molecule. This minor difference has if at all only a slight effect on substance properties. Thus it is justified to use n-butyl acetate as supporting substance in assessing toxicological effects of isobutyl acetate. Further details on read-across justification can be found in the read-across documentation in section 13.

 

Thus, the LC50 of isobutyl acetate is assessed to be 30 mg/L as determined in the study of Smyth and confirmed by cross reading from the results for the supporting substance n-butyl acetate (weighth-of-evidence approach).

 

Smyth 1962

 

For this acute inhalation toxicity study, a standard graduate dose test and an inhalation hazard test were performed. The observation period for both tests was 14 days.

 

Groups of six female albino rats were exposed for 4 hours to graduate doses of isobutyl acetate vapor in the breathing atmosphere of test animals (4000, 8000, and 16000 ppm; 19.3, 38.6, and 77.3 mg/L respectively).

 

In the inhalation hazard test, test animals were exposed for various time periods starting from one forth hour up to 8 hours (spacing factor of 2) to an atmosphere saturated or close to saturation with vapors of isobutyl acetate (saturated vapor concentration ca. 95 mg/L).

 

Nominal concentrations were not analytically verified.

 

In the standard test, concentrations of 19.3, 38.6, and 77.3 mg/L caused mortality of 0, 4, and 6 out of 6 animals, respectively.

 

In the inhalation hazard test (saturated vapor), the exposure time was restricted to 1 hour in order to produce no mortality.

 

From the mortality data, the LC50 of isobutyl acetate is estimated to be 30 mg/L in rats (Smyth, 1962).

 

OPP/CMA 1994 - read-across from n-butyl acetate

 

In an acute inhalation neurotoxicity study, 10 Sprague-Dawley rats per sex per group were exposed to concentrations of 0, 1500, 3000, and 6000 ppm (0, 7.2, 14.5, and 29 mg/L) of n-butyl acetate for a single 6 h period followed by an observation period of 14 days. To assess the neurotoxicity of n-butyl acetate a motor activity test and a functional observation battery (FOB) were performed. Clinical signs were recorded, body weights were measured, and gross pathological examinations were performed at the end of the study.

 

No mortality was observed during the study. Clinical signs were only observed during exposure (hypoactivity, sialorrhea, occasionally tearing). No clinical signs were noted at any time post-exposure. No exposure-related changes were noticed at gross pathology.

 

Mortality data demonstrate that LC50 of n-butyl acetate is > 30 mg/L in rats (highest dose tested; LC0 = 30.2 mg/L) (OPP/CMA, 1994).

 

BASF 1988 - read-scross from n-butyl acetate

 

In an acute inhalation toxicity study, groups of young adult male and female wistar rats (5 animals in each group) were exposed by inhalation route (nose/head only) to n-butyl acetate (99.5%) for 4 hours at concentrations of 1.97 (test group 1) and 23.4 mg/L (test group 2). Animals were then observed for 14 days. In particle size analysis, no aerosol particles were detectable.

 

In test group 2, clinical signs of toxicity were observed at the day of exposure (during exposure and thereafter). From day 1 onward, no abnormalities were detected. Pathological lesions (focal atelectasis in all lobes of the lung) were only detected in three animals (1 male, 2 females) of test group 2.

 

Under test conditions, no death occurred.

 

Based on mortality at the highest dose tested, LC50 of n-butyl acetate can be determined to be > 23.4 mg/L in rats (highest dose tested, LC0 = 23.4 mg/L; statistical reliability 99.9%) (BASF, 1988).

 

Acute toxicity: dermal

 

For assessment of the acute dermal toxicity of isobutyl acetate, only one valid study is available (Smyth, 1962, RL2, pre-GLP study, similar to OECD TG 402). The publication of Opdyke/Moreno (1978, RL4) is a review article reporting toxic effects of isobutyl acetate in summary (secondary source).

 

Smyth (1962)

 

The acute dermal toxicity of isobutyl acetate was determined in groups of 4 male albino New Zealand rabbits. The exposure time was 24 hours followed by an observation period of 14 days. Overall, the study was conducted similar to OECD test guideline 403 with some restrictions (only 4 animals per group, occlusive wrapping, limited reporting).

 

The acute dermal LD50 of isobutyl acetate was > 17400 mg/kg bw in rabbits (Smyth, 1962).

In the less reliahble study cited from secondary source the acute dermal toxicity of isobutyl acetate in rabbits is reported to be > 5000 mg/kg bw (Opdyke/Moreno, 1978).

Justification for selection of acute toxicity – oral endpoint
Low LD50 reported from adequate study of high reliability (Klimisch score 2).

Justification for selection of acute toxicity – inhalation endpoint
No single study was selected as endpoints conclusion was reached in a weighth-of-evidence approach based on the results obtained in various studies.

Justification for selection of acute toxicity – dermal endpoint
Low LD50 reported from adequate study of high reliability (Klimisch score 2).

Justification for classification or non-classification

Acute oral toxicity

 

The LD50 in rats was determined to be 13413 mg/kg bw. This exceeds by far the cut-off value of 2000 mg/kg bw for hazard category 4 of the regulation (EC) 1272 /2008. No classification is required.

 

Acute inhalation toxicity

 

The LC50 in rats was determined to be 30 mg/L. This exceeds by far the cut-off value of 20 mg/L for hazard category 4 of the regulation (EC) 1272/2008. No classification is required.

However based on this LC50 value of 30 mg/L classification into acute oral toxicity category 5 is required according to United Nations GHS, 2013 (ST/SG/AC.10/30/Rev.5). 

 

Acute dermal toxicity

 

The LD50 in rabbits was determined to be > 17400 mg/kg bw. This exceeds by far the cut off value of 2000 mg/kg bw for hazard category 4 of the regulation (EC) 1272/2008. No classification is required.

 

Synopsis

 

The acute oral, inhalation, and dermal toxicity of isobutyl acetate is low and does not require classification according to EU regulation.