2-Butanone, peroxide

Endpoint summary

Description of key information

Methyl-ethylketone peroxide was tested for acute toxicity by oral, inhalation and dermal application to the rat and mice. The LD50 (oral, male) was 1017 mg/kg bw. The LC50 (4h, inhalation) was 17 mg/L. The combined dermal LD50 was 4000 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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

see below

Principles of method if other than guideline:

Thirty male rats of Charles River CD strain, weighting 200 to 260 grams, were divided equally into 6 groups. Single, oral doses of the test material, suspended in corn oil, were administered to rats that were fasted overnight. Observations for mortality were recorded daily for 14 days.

GLP compliance:

not specified

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Charles River CD

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200 to 260 g
- Fasting period before study: fasting overnight

Route of administration:

oral: unspecified

Vehicle:

corn oil

Doses:

508.1, 807.1, 1281, 2034, 3229, 5126 mg/kg bw

No. of animals per sex per dose:

5 male rats per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: no
- Other examinations performed: body weight

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1 017 mg/kg bw

Based on:

test mat.

95% CL:

>= 879 - <= 1 175

Mortality:

No mortality was shown up to doses level 807.1 mg/kg bw. All other animals were dead up to days 1. Details see in the field "Any other information on results incl. tables".

Dose levels (mg/kg bw)	Number of dead animals	Total moralities	hours	days
508.1	0/4
807.1	0/5
1281	0/5
2034	5/5
3229	5/5
5126	5/5

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral toxicity (LD50) value for methyl-ethylketone peroxide in DMP in male albino rats was calculated to be 1017 (879 - 1175) mg/kg.

Executive summary:

Methyl-ethylketone peroxide in DMP was tested in an acute oral toxicity study to thirty male rats of Charles River CD strain.

The thirty animals were divided equally into 6 groups. Single, oral doses of the test material, suspended in corn oil, were administered to rats that were fasted overnight. Observations for mortality were recorded daily for 14 days.

The acute oral toxicity (LD50) value for methyl-ethylketone peroxide in male albino rats was calculated to be 1017 (879 - 1175) mg/kg .

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 017 mg/kg bw

Quality of whole database:

Non-GLP and non-guideline study, but sufficient for assessment.

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

Study period:

1979-05-09 to 1979-06-14

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

old study report, non GLP and non Guideline study, but well documented. For justification of read across please refer to section 13.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Weight at study initiation: males: 180 g, females: 135 g
- Fasting period before study: none
- Housing: 5 animals per cage, stainless steel cages
- Diet: ad libitum the Institute's stock diet for rats
- Water: ad libitum unfluoridated water

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 1 °C
- Humidity (%): 50 - 60

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel exposure chamber
- Exposure chamber volume: 1.5 m3
- Source and rate of air: total airflow of 1.6 m3/h
- System of generating particulates/aerosols: nebulizer provided with a baffle to remove large rdroplets from the mist produced
- Method of particle size determination: particle size determinations and counts were carried out in samples taken from the atmosphere in the chamber with a Cascade Impactor

TEST ATMOSPHERE
- Brief description of analytical method used: analysis of the test atmosphere was performed gravimetrically, samples were takne by passing a measured quantity of the test atmosphere through a Cambridge glassfibre filter at intervals of about 1.5 h
- Samples taken from breathing zone: yes
- Particle size distribution: maximum diameter 6.7 µm, 80 % of the mist consisted of droplets with a diameter of 1.7-3.3 µm

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

2.56, 1.77, 1.55, 1.38, 1.30 g/m3 (measured)

No. of animals per sex per dose:

5

Control animals:

no

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

1 500 mg/m³ air

Based on:

test mat.

95% CL:

> 1 400 - < 1 610

Exp. duration:

4 h

Mortality:

All animals of the highest dose group died until day 4 as well as 2 males and all females of the 1.77 g/m3 dose group, 3 males and 4 females of the 1.55 g/m3 dose group, 2 males and 2 females of the 1.38 g/m3 dose group and 2 males of the lowest (1.3 g/m3) dose group.

Clinical signs:

other: Restlessness during the first half an hour was observed. During exposure, animals kept their eyes closed and some had wet noses. After exposure mouth breathing was observed in the higher doses.

Body weight:

Animals lost weight during the first week of observation period. Surviving animals gained weight during the second week.

Gross pathology:

no data

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on the LC 50 value of 1.5 g/m3 (1.5 mg/L) the read across-substance has to be classified for acute toxicity after inhalation into category 4.

Executive summary:

The acute inhalation toxicity of the read across-substance (60 % in Di-isobutyl phthalate) was tested on 50 male and 50 female Wistar rats. The animals were individually exposed to the aerosol at concentrations of 2.56, 1.77, 1.55, 1.38 and 1.30 g/m3 (5 males anf 5 females per doese group) for 4 hours. The animals were observed for a period of 14 days afterwards. All animals of the highest dose group died until day 4 as well as 2 males and all females of the 1.77 g/m3 dose group, 3 males and 4 females of the 1.55 g/m3 dose group, 2 males and 2 females of the 1.38 g/m3 dose group and 2 males of the lowest (1.3 g/m3) dose group. Restlessness during the first half an hour of exposure was observed. During exposure, animals kept their eyes closed and some had wet noses. After exposure mouth breathing was observed in the higher doses. A weight loss was observed during the first week of the observation period, but the surviving animals gained weight again in the second week. An LC 50 value of 1.5 mg/L was detemined.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

17 000 mg/m³ air

Quality of whole database:

Non-GLP and non-guideline studies, but sufficient for assessment.

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:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

see below

Principles of method if other than guideline:

The hair was clipped from the back of each rabbit. The skin was abraded for 1/2 of the rabbits in each group. The rabbits were equally in 4 dosage levels (1000, 2000, 4000 and 8000 mg/kg). The test material was applied, to the backs in appropriate doses. The site of application was covered with gauze bandaging and occluded with Saran Wrap.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2317 to 2548 grams

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

The skin was abraded for 1/2 of the rabbits in each group. The test material was applied, to the backs in appropriate doses. The site of application was covered with gauze bandaging and occluded with Saran Wrap.

Doses:

1000, 2000, 4000 and 8000 mg/kg

No. of animals per sex per dose:

1 animal per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: The rabbits were observed for death at 24 hours and daily thereafter for a total of 14 days.
- Necropsy of survivors performed: no

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 000 mg/kg bw

Based on:

test mat.

95% CL:

2 000 - 8 000

Mortality:

Three animals died on day 1. (Details see "any other information on results incl. tables".)

Table: Dose - Mortality Table

Dose levels (mg/kg)	Number of deaths		Mortality incidence
	days
	1	2	Male	Female	Total
1000			0/1	0/1	0/2
2000			0/1	0/1	0/2
4000	1		0/1	1/1	1/2
8000	2		1/1	1/1	2/2

Interpretation of results:

GHS criteria not met

Conclusions:

The calculated actue dermal toxicity (LD50) value in male and female albino rabbits was found to be 4000 (2000 - 8000) mg/kg.

Executive summary:

Methyl-ethylketone peroxide in DMP was tested in a acute dermal study to eight New Zealand White rabbits, equally divided as to sex in 4 groups. The hair was clipped from the back of each rabbit. The skin was abraded for 1/2 of the rabbits in each group. The dosage levels were 1000, 2000, 4000 and 8000 mg/kg. The test material was applied to the backs in appropriate doses. The site of application was covered with gauze bandaging and occluded with Saran Wrap.

The rabbits were observed for death at 24 hours and daily thereafter for a total of 14 days.

The calculated actue dermal toxicity (LD50) value in male and female albino rabbits was found to be 4000 (2000 - 8000) mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

4 000 mg/kg bw

Quality of whole database:

Non-GLP and non-guideline study, but sufficient for assessment.

Additional information

Acute toxicity oral:

Methyl-ethylketone peroxide in DMP was tested in an acute oral toxicity study to thirty male rats of Charles River CD strain (evaluated as Klimisch 2).

The thirty animals were divided equally into 6 groups. Single, oral doses of the test material, suspended in corn oil, were administered to rats that were fasted overnight. Observations for mortality were recorded daily for 14 days.

The acute oral toxicity (LD50) value for methyl-ethylketone peroxide in male albino rats was calculated to be 1017 (879 - 1175) mg/kg .

A study cited in the literature revealed a LD50 of 484 mg/kg bw: However as neither information on test conditions nor information on test substance are available the study is evaluated as Klimisch 3 and not considered for the hazard assessment of methyl-ethylketone peroxide.

Acute toxicity dermal:

Methyl-ethylketone peroxide in DMP was tested in a acute dermal study to eight New Zealand White rabbits (evaluated as Klimisch 2).

The hair was clipped from the back of each rabbit. The skin was abraded for 1/2 of the rabbits in each group. The rabbits were divided equally in 4 dosage levels. The dosage levels were 1000, 2000, 4000 and 8000 mg/kg. The test material was applied to the backs in appropriate doses. The site of application was covered with gauze bandaging and occluded with Saran Wrap.

The rabbits were observed for death at 24 hours and daily thereafter for a total of 14 days.

The calculated acute dermal toxicity (LD50) value in male and female albino rabbits was found to be 4000 (2000 - 8000) mg/kg.

Acute toxicity inhalation:

Two studies were used in a weight of evidence approach for evaluation of the acute inhalation toxicity of Methyl-ethylketone peroxide.

The first study was carried out with the read across-substance Methyl isobutyl ketone peroxide (MIBKP) (60 % in diisobutyl phthalate). The substance was tested on 50 male and 50 female Wistar rats. The animals were individually exposed to the aerosol at concentrations of 2.56, 1.77, 1.55, 1.38 and 1.30 g/m3 (5 males anf 5 females per dose group) for 4 hours. The animals were observed for a period of 14 days afterwards. All animals of the highest dose group died until day 4 as well as 2 males and all females of the 1.77 g/m3 dose group, 3 males and 4 females of the 1.55 g/m3 dose group, 2 males and 2 females of the 1.38 g/m3 dose group and 2 males of the lowest (1.3 g/m3) dose group. Restlessness during the first half an hour of exposure was observed. During exposure, animals kept their eyes closed and some had wet noses. After exposure mouth breathing was observed in the higher doses. A weight loss was observed during the first week of the observation period, but the surviving animals gained weight again in the second week. An LC 50 value of 1.5 mg/L was detemined. The substance has thus to be classified for acute inhalation toxicity into category 4.

In the second study, Methyl-ethylketone peroxide in DMP was also tested in an acute inhalation toxicity study to rats (evaluated as Klimisch 4). Sixty (30 male and 30 female) albino rats of the Charles River CD strain were divided equally into 6 dosage groups. The concentrations of the test substance are 6.25, 12.5, 25.0, 50.0, 100.0 and 200.0 mg/L. Each group of rats was placed in a sealed 59.1 litre glass chamber and exposed to the appropriate level of test material for 4 hours. Observations for pharmacodynamic signs and mortality were made during the exposure and daily thereafter for 14 days. The calculated LC50 -values were 15.4 (9.9 -23.9) mg/L for male rats, 19.3 (15.5 - 23.9) mg/L for female rats and 17 (13.-22.2) mg/L for male and female rates together. No information is given whether the substance was tested as aerosol or vapour.

According to the ECHA-Guidance document on the Application of the CLP Criteria (Version 4.0 – November 2013), the differentiation can be done using the following equation:

SVC [mg/L] = 0.0412 x molecular weight x vapour pressure (vapour pressure in hPa at 20°C).

If the SVC value is well below the LC50 value, the guidance document advises to classify according to the criteria for aerosols. In this case, calculating the SVC with the data for the most volatile isomer of MEKP, it is well below the LC 50 value (SVC = 5.31 mg/L, LC50 = 17 mg/L). However, classification according to the criteria for vapours seems to be more appropriate based on the structure of MEKP and the expected vapour pressure when compared to the data for MIBKP. MEKP molecules are smaller than MIBKP molecules, therefore the vapour pressure of MEKP is expected to be higher. Thus, the classification criteria for vapours were applied for the assessment of the inhalation toxicity of MEKP and the substance is also classified for acute inhalation toxicity into category 4.

In two additional supporting studies, inhalation of methyl-ethylketone peroxide in DMP for 4 hours produced an LC50 of 200 ppm for rats and 170 ppm for mice. Pathologic findings included hyperemia of the lungs, with petechial hemorrhages on the lungs surface in some animals and gross hemorrhages in others. Nasal pyrphyrin exudate occurred occasionally in acute intraperitoneal and inhalation studies.

Other routes:

A single intraperitoneal injection of methyl-ethylketone peroxide in DMP in rats led to prostration, followed by death; the LD50 was estimated to be 65 mg/kg for methyl-ethylketone peroxide in DMP (Zeiger, E., 1993).

In rats injected with about one-fifth the LD50 (i.e. 15 mg methyl-ethylketone peroxide/kg of body weight) 3 times per week for 7 weeks, the liver was mildly damaged and showed depletion of glycogen, but showed no dissociation of liver cells (Zeiger, E; 1993).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on acute oral toxicity, the test item is classified and labelled with acute tox 4 oral and inhalation (H302, harmful if swallowed; H332, harmful if inhaled) according to Regulation (EC) No 1272/2008 (CLP), as amended for the seventeenth time in Regulation (EU) No 2021/849.