4-methylpent-3-en-2-one

Endpoint summary

Description of key information

The acute oral LD50 of Mesityl oxide was greater than 300 but less than 2000 mg/kg body weight (OECD 423). A weight of evidence approach based on pre-guideline studies identified a 4-hr LC50 of 1130 ppm (4530 mg/m3) in rats. The acute dermal LD50 was reported to be 5150 mg/kg for the rabbit.

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:

2010

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:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Italy
- Age at study initiation: 9-10 weeks
- Weight at study initiation: approx. 200-250 gr
- Fasting period before study: Overnight prior to dosing (Day –1) up to 4 hours after dosing.
- Housing: 5 if 1 sex/cage during acclimatisation; 3 if 1 sex/cage during study
- Diet (e.g. ad libitum): with the exception of the fasting procedure described above
- Water (e.g. ad libitum):
- Acclimation period: aproximately 3-4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 2°C
- Humidity (%): 55% ± 15%
- Air changes (per hr): Approximately 15 to 25 air changes per hour
- Photoperiod (hrs dark / hrs light): Artificial (fluorescent tubes), daily light/dark cycle of 12/12 hours

IN-LIFE DATES: From: 3-jun-2010 To: 29-jun-2010

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5 % in water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 and 30 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg

Doses:

300 and 2000 mg/kg

No. of animals per sex per dose:

3 female animals at 2000 mg/kg
6 female animals at 300 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy performed: yes (including early decedent)
- Other examinations performed: clinical signs, body weight

Statistics:

None

Preliminary study:

A first sub-group of three female animals was dosed at 2000 mg/kg body weight (step 1). The three animals were found dead at 30 minutes, 4 hours after dosing and, the last one, on Day 2. The clinical signs recorded on the day of dosing were: salivation, lachrymation, difficult breathing, lack of consciousness, mucosal reddening. At necropsy examination, no abnormalities were recorded with the exception of a single animal (died between 2 and 4 hours post dose) which showed abnormal, clear content in the stomach.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Mortality:

2000 mg/kg: 3/3 animals. The three animals were found dead at 30 minutes, 4 hours after dosing and, the last one, on Day 2
300 mg/kg: 0/6 animals.

Clinical signs:

other: 2000 mg/kg: salivation, lachrymation, difficult breathing, lack of consciousness, mucosal reddening. 300 mg/kg: lethargy (or, later, hunched posture), reduced activity lachrymation, semiclosed eyes and piloerection. Presence of clinical signs arose at 30

Gross pathology:

2000 mg/kg: no abnormalities were recorded with the exception of a single animal (died between 2 and 4 hours post dose) which showed abnormal, clear content in the stomach.
300 mg/kg: no abnormalities were recorded at post mortem examination.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

These results indicate that the test item, Mesityl oxide, has severe toxic effects at 2000 mg/kg while some toxic effect, shortly reversible, were observed following oral administration of a single dose at a level of 300 mg/kg.
The mortality pattern demonstrates the LD50 to be greater than 300 but less than 2000 mg/kg body weight.

Executive summary:

The acute toxicity of Mesityl oxide (purity 99.87%) was investigated after a single oral administration to female Sprague Dawley rats followed by a 14-day observation period (Dose volume: 10 ml/kg; Vehicle:0.5% carboxymethylcellulose acqueous solution). The animals were sacrificed at the end of the observation period and subjected to necropsy examination. A first sub-group of three female animals was dosed at 2000 mg/kg body weight (step 1). The three animals were found dead at 30 minutes, 4 hours after dosing and, the last one, on Day 2. The clinical signs recorded on the day of dosing were: salivation, lachrymation, difficult breathing, lack of consciousness, mucosal reddening. At necropsy examination, no abnormalities were recorded with the exception of a single animal (died between 2 and 4 hours post dose) which showed abnormal, clear content in the stomach. Two sub-groups of three female animals were subsequently dosed at 300 mg/kg body weight (steps 2 and 3). In step 2, the following clinical signs were recorded: lethargy (or, later, hunched posture), lachrymation, semiclosed eyes and piloerection. In step 3, clinical signs were as follows: hunched posture, reduced activity, lachrymation and piloerection. In both steps, presence of clinical signs arose at 30 minutes after dosing. Recovery started from 4 hours after dosing and was completed by Day 2. No toxicologically relevant effects on the body weight gain were observed and no abnormalities were recorded at post mortem examination in these animals. These results indicate that Mesityl oxide, has severe toxic effects at 2000 mg/kg while some toxic effect, shortly reversible, were observed following oral administration of a single dose at a level of 300 mg/kg. The mortality pattern demonstrates the LD₅₀to be greater than 300 but less than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

discriminating dose

Value:

300 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Principles of method if other than guideline:

Pre-guideline study.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Long-Evans

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 70-150g

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass chamber
- Exposure chamber volume: no data
- Method of holding animals in test chamber: no data
- Source and rate of air: 6 l/min
- Method of conditioning air: no data
- System of generating vapours: the compound was introduced by means of a syringe oparating at a constant rate. A heating coil was used to vaporize the undiluted liquid.
- Temperature, humidity, pressure in air chamber: no data

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Concentrations:

450, 900, 1800 and 3600 ppm

No. of animals per sex per dose:

6

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days

Sex:

male

Dose descriptor:

LC50

Effect level:

1 130 ppm

95% CL:

950 - 1 345

Exp. duration:

4 h

Remarks on result:

other: 4.53 mg/l

Mortality:

450 ppm, no death
900 ppm, 1 death
1800 ppm, 6 deaths occuring within 24 hours
3600 ppm, 6 deaths during or shorthly after exposure

Clinical signs:

other: 450 and 900 ppm, mild eye irritation 1800 ppm, moderate eye irritation and marked vasodilatation. 3600 ppm, severe disconfort and pulmonary diffculty, most rats became comatose after 2 hours

Body weight:

no data

Gross pathology:

no data

Interpretation of results:

toxic

Remarks:

Migrated information category 3 Criteria used for interpretation of results: other: Regulation (EC) No 1272/2008

Executive summary:

Hine et al. (1960) determined the 4-hr LC50 in rats to be 1130 ppm.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

4 530 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

other: publication

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Type of coverage:

not specified

Vehicle:

not specified

Details on dermal exposure:

No data

Duration of exposure:

No data

Doses:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Statistics:

No data

Sex:

not specified

Dose descriptor:

LD50

Effect level:

5 150 mg/kg bw

95% CL:

> 4 260 - < 8 420

Mortality:

No data

Clinical signs:

other: No data

Gross pathology:

No data

Interpretation of results:

not classified

Remarks:

Migrated information

Executive summary:

The acute dermal LD50 was reported to be 5150 mg/kg for the rabbit.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

5 150 mg/kg bw

Additional information

Oral route

In an OECD 423 study, the acute toxicity of Mesityl oxide (purity 99.87%) was investigated after a single oral administration to female Sprague Dawley rats followed by a 14-day observation period (Dose volume: 10 ml/kg; Vehicle:0.5% carboxymethylcellulose acqueous solution) (Corvaro, 2010a). The animals were sacrificed at the end of the observation period and subjected to necropsy examination. A first sub-group of three female animals was dosed at 2000 mg/kg body weight (step 1). The three animals were found dead at 30 minutes, 4 hours after dosing and, the last one, on Day 2. The clinical signs recorded on the day of dosing were: salivation, lachrymation, difficult breathing, lack of consciousness, mucosal reddening. At necropsy examination, no abnormalities were recorded with the exception of a single animal (died between 2 and 4 hours post dose) which showed abnormal, clear content in the stomach. Two sub-groups of three female animals were subsequently dosed at 300 mg/kg body weight (steps 2 and 3). In step 2, the following clinical signs were recorded: lethargy (or, later, hunched posture), lachrymation, semiclosed eyes and piloerection. In step 3, clinical signs were as follows: hunched posture, reduced activity, lachrymation and piloerection. In both steps, presence of clinical signs arose at 30 minutes after dosing. Recovery started from 4 hours after dosing and was completed by Day 2. No toxicologically relevant effects on the body weight gain were observed and no abnormalities were recorded at post mortem examination in these animals. These results indicate that Mesityl oxide, has severe toxic effects at 2000 mg/kg while some toxic effect, shortly reversible, were observed following oral administration of a single dose at a level of 300 mg/kg. The mortality pattern demonstrates the LD₅₀ to be greater than 300 but less than 2000 mg/kg body weight.

Inhalation

Hine et al. (1960) determined the 4-hr LC50 in rats and mice to be 1130 (4530 mg/m3) and 2000 to 4000 ppm, respectively.

Smyth et al. (1942) found that 12,000 ppm mesityl oxide killed rats and guinea pigs after 1 hr of exposure. Eight-hour exposures of rats to 2500, 1000, and 500 ppm killed 100, 68, and 30 percent of the test animals, respectively.

Hart et al. (1939) exposed mice to concentrations of 6000 to 24,000 ppm mesityl oxide in air. Clinical signs of toxicity were ocular and nasal irritation, labored breathing, convulsions, narcosis, vasodilation, cyanosis, and death. The time to death was concentration dependent, and ranged from 23 to 135 min.

Carpenter et al. (1949) subjected groups of six male or female rats to acute 4-hr exposures of increasing concentrations of mesityl oxide until two to four of the animals died within a 14-day observation period. They found that a concentration of 1000 ppm was necessary to produce this mortality.

Dermal route

The acute dermal LD50 was reported to be 5150 mg/kg for the rabbit (Topping et al., 1994).

Justification for selection of acute toxicity – oral endpoint
GLP guideline study

Justification for selection of acute toxicity – inhalation endpoint
Weight of evidence approach

Justification for selection of acute toxicity – dermal endpoint
Only data available. Data from handbook or collection of data

Justification for classification or non-classification

Regulation (EC) No 1272/2008

Annex VI Table 3.1

Classification		Labelling
Hazard Class and Category Code(s)	Hazard Statement Code(s)	Pictogram Signal Word Code(s)	Hazard Statement Code(s)	Suppl. Hazard statement code(s)
Acute Tox. 4 * Acute Tox. 4 * Acute Tox. 4 *	H332 H312 H302	GHS07 Wng	H332 H312 H302

Annex VI Table 3.2

Classification	Risk phrases	Indication(s) of danger
Xn; R20/21/22	20/21/22	Xn

Concentration Limits
Concentration	Classification
C = 5 %	Xn; R20/21/22

Proposed self classification

According to Regulation (EC) No 1272/2008

Classification		Labelling
Hazard Class and Category Code(s)	Hazard Statement Code(s)	Pictogram Signal Word Code(s)	Hazard Statement Code(s)	Suppl. Hazard statement code(s)
Acute Tox. 3 Acute Tox. 4	H331 H302	GHS06	H331 H302

According to Directive 67/548/EEC

Classification	Risk phrases	Indication(s) of danger
Xn; R20/22	20/22	Xn