Isopropyl 2-methylbutyrate

Endpoint summary

Description of key information

On the basis of read across it is not classified for acute inhalation (LC50 5967 mg/m3) or dermal toxicity (LD50 >2000 mg/kg bw).

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

Study period:

21 May to 08 June 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

not specified

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

not specified

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: HanIbm: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Biotechnology & Animal Breeding Division
- Age at study initiation: Females: 10 weeks, Males: 8 weeks
- Weight at study initiation:
- Fasting period before study: approximately 16.5 to 18.5 hours, but with free access to water. Food was provided again approximately 3 hours after dosing.
- Housing: Groups of three in Makrolon type-4 cages with standard softwood bedding
- Diet: Pelleted standard Kliba 3433, rat maintenance diet (Provimi Kliba AG,) available ad libitum (except for the overnight fasting period prior to intubation).
- Water: Community tap water, available ad libitum.
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40 - 70% (relative humidity)
- Air changes (per hr): 10 - 15 (air-conditioned)
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

other: PEG 300

Doses:

Dose: 2000mg/kg bw
Application volume: 10ml/kg bw

No. of animals per sex per dose:

3 females, 3 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/Viability and Clinical Signs: Four times during test day 1 and once daily during days 2-15; Body weights: On test day 1 (pre-administration), 8 and 15; Room environment was monitored continuously with hourly recordings
- Necropsy of survivors performed: yes
- Other examinations performed: no

Statistics:

No statistical analysis was used as no deaths occurred.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No death occurred during the study.

Clinical signs:

No clinical signs were observed during the study period.

Body weight:

Sex Animal No. Day of Treatment Day 8 Day 15

Female 1 187.1 205.5 217.1
2 184.9 207.6 226.8
3 188.9 216.6 227.4

Male 4 205.9 270.8 293.4
5 218.5 274.8 301.8
6 212.4 258.5 273.9

Gross pathology:

No macroscopic findings were observed at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose of Isopropyl methyl-2-butyrate after single oral administration to rats of both sexes, observed over a period of 14 days, could not be estimated as no death occurred.

LD50 rat: greater than 2000 mg/kg body weight

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

29 April to 19 May 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The substance is an analogue of IMB

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source and target substances have similar purities and few impurities.

3. ANALOGUE APPROACH JUSTIFICATION
All three substances are Cramer class 1 (simple chemical structure with low order oral toxicity with a toxicological threshold of 1800µg/person/day or 30µg/kg bw/day) and have similar chemical and physico-chemical properties, being short chain aliphatic esters. Each is rapidly hydrolysed by esterases to form constituent alcohols and carboxylic acids which become substrates for β-oxidation. For each substance, toxicological endpoint classification is identical for acute oral toxicity, skin irritation and mutagenicity (point mutation, gene mutation and structural chromosomal aberrations).

In light of the structural and physico-chemical similarities between EMB, EMV and IMB it is our consideration that experimental testing for an acute inhalation repeated dose toxicity study using IMB can be waived, as study data from the structurally related esters EMB and EMV can be used to read-across and predict the toxicity of IMB.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

fixed concentration procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Toyo Gosei / H3-G-26
- Expiration date of the lot/batch: 25 July 2014
- Purity test date: No data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In original container at 2° to 8°Cin the dark.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Animal breeding facility
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 10-11 weeks
- Weight at study initiation: male 285 to 303g and female 199 to 204g
- Fasting period before study: no data
- Housing: polypropylene rat cages covered with stainless steel grid tops
- Diet: High Fiber feed ad libitum
- Water: UV sterilised ad libitum
- Acclimation period: 26 hours

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19° to 22°C
- Humidity (%): 64 to 65%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12:12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose/head only

Vehicle:

not specified

Mass median aerodynamic diameter (MMAD):

ca. 1 - ca. 4 µm

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: ht 30cm; 30cm internal diameter;
- Exposure chamber volume: 63.5 litres
- Method of holding animals in test chamber: single transparent perspex exposure tube.
- Source and rate of air: 15 changes per hour.
- Method of conditioning air: no data
- System of generating particulates/aerosols: spray atomiser
- Method of particle size determination: seven-stage cascade impactor
- Treatment of exhaust air: passes through 1.0% sodium hydroxide and moisture traps containing silica gel.
- Temperature, humidity, pressure in air chamber: 22.4 to 22.6°C; 43.7 to 44.4% RH. A slight negative pressure was maintained inside the chamber by keeping the air outflow rate slightly more than the air inflow rate, to prevent leakage of the test item into the surrounding area.

TEST ATMOSPHERE
- Brief description of analytical method used: open face sampler with glass microfibre papers
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): not applicable.

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:
- MMAD (Mass median aerodynamic diameter): 1 to 4µm

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Remarks on duration:

In addition to the 4 hour exposure there was a 15 minute equilibration period.

Concentrations:

5.967 mg / l air

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: day 1, 3, 7 and 14.
- Necropsy of survivors performed: yeso
- Other examinations performed: clinical signs, body weight,organ weights, histopathology,

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.967 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

None

Clinical signs:

other: None

Body weight:

Mean body weight of rats post-exposure equalled or increased on days 1, 3, 7 and 14 in both sexes of rats when compared with pre-exposure (day 0) mean body weight.

Gross pathology:

Visceral examination did not reveal any lesions of pathological significance.

Interpretation of results:

GHS criteria not met

Conclusions:

On the basis of the results of this study ethyl 2-methylvalerate was found to be non-toxic and will not be classified for inhaltion toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 967 mg/m³

Quality of whole database:

Klimisch 1

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

Study period:

03 May and 11 May 2000

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source and target chemicals are analagous

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source and target chemicals are both pure with low impurity.

3. ANALOGUE APPROACH JUSTIFICATION
In light of the structural and physico-chemical similarities between EMB, EMV and IMB it is our consideration that experimental testing for an acute dermal repeated dose toxicity study using IMB can be waived, as study data from the structurally related esters EMB and EMV can be used to read-across and predict the toxicity of IMB.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 20010036

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: approx. 4°C in the dark.

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent
- Age at study initiation: approximately 8 to 12 weeks old
- Weight at study initiation: males weighed 222 to 231g, and the females 215 to 226g
- Fasting period before study: No details provided in report
- Housing: The animals were housed in suspended polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-hour exposure period and in groups of five, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): Free access to mains drinking water and food (Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study.
- Water (e.g. ad libitum): Free access to mains drinking water and food (Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK) was allowed throughout the study.
- Acclimation period: minimum acclimatisation period of five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
(Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study).
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12 hours continuous light and 12 hours darkness

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- The calculated volume of the test material, as received, was applied uniformly to an area of shorn skin (approximating to 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. The animals were caged individually for the 24-hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material. The animals were returned to group housing for the remainder of the study period.
- Time after start of exposure: After the 24-hour contact period

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Dose volume 2.33 ml/kg and Specific gravity 0.861 (Dose level 2000 mg/kg)

Duration of exposure:

24 hours

Doses:

Dose volume: 2.33 ml/kg
Specific gravity: 0.861
Dose level: 2000 mg/kg

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: The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. Individual bodyweights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: At the end of the study the animals were killed by cervical dislocation and subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
- Other examinations performed: After removal of the dressings and subsequently once daily for 14 days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) “Dermal and Eye Toxicity Tests” In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31 (see attached report for details). Any other skin reactions, if present were also recorded.

Statistics:

No details provided in report

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths

Clinical signs:

No clinical signs of toxicity were noted during the study.

Body weight:

All animals showed expected gain in bodyweight during the study.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

No signs of dermal irritation were noted during the study.

Interpretation of results:

practically nontoxic

Conclusions:

The acute dermal median lethal dose (LD50) of the test material, ETHYL METHYLBUTYRATE-2, in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. No symbol and risk phrase are required according to EU labelling regulations.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1

Justification for classification or non-classification

On the basis of read across it is not classified for acute oral (LD50 > 2000 mg / kg bw).