2,4-dimethylpentan-3-one

Endpoint summary

Description of key information

The oral LD50 of the test material was determined to be 3645 mg/kg bw.

The inhalation LC50 of the test material was determined to be > 2765 ppm for a 6h-exposure.

2765 ppm is the highest vapour concentration that can be achieved without generation of an additional aerosol phase.

During the exposure, the according test group exhibited severe narcosis and moderate dyspnea. Immediately after the exposure, all male and female animals from this group had unkempt facial haircoats and exhibited minor to severe narcosis, hypothermia, and excessive tearing.

Based on a study with a non-characterized test atmosphere, the LC50 was approximately 68 mg/L (4/6 rats died) for a 1h-exposure. For the 4h-exposure period, this translates to an LC50 of approximately 17 mg/L.

The dermal LD50 of the test material was determined to be 16200 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)

Principles of method if other than guideline:

A test group consisting of 5 animals/sex was treated by single gavage application with an aqueous solution of the test substance (6400, 5000, 4500, 4000, 3200 µL/kg via an emulsion containing 30 % test substance). The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observation period also were subjected to necropsy.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in report): 2,4-Dimethylpentanon-3 / Diisopropyl keton
- Physical state: liquid

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Gassner

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation (mean): Males 216 g, females 179 g

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

Aquatic emulsion with CMC and 2-3 drops Cremophor EL

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 % v/v

MAXIMUM DOSE VOLUME APPLIED: 6400 µL/kg

Doses:

6400, 5000, 4500, 4000, 3200 µL/kg (Conc. 30 %)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
Other examinations performed: clinical signs, body weight

Statistics:

LD50 calculation according to LITCHFIELD und WILCOXON

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 645 mg/kg bw

Based on:

act. ingr.

Remarks on result:

other: based on a relative density of 0.81

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4.5 mL/kg bw

Based on:

act. ingr.

Mortality:

At 6400 µL/kg bw: 4/5 male and 3/ female animals died within 1 hour after dosing. All male animals were dead within 7 days and all female animals within 48 hours.
At 5000 µL/kg bw: 1/5 male and 1/5 female animals died within 24 hours after dosing. All male animals and 4/5 female animals were dead within 7 days. The last surviving female animal died in the last week of observation (within 14 days).
At 4500 µL/kg bw: 1 male animal died within the 14 day observation period. 1/5 female animals died with 48 hours after dosing and 4/5 died within 7 days after dosing. The last surviving female animal died in the last week of observation (within 14 days).
4000 µl/kg bw: no mortality occurred
3200 µl/kg bw: no mortality occurred

Clinical signs:

other: Immediately after application accelerated breathing was observed. Depending on the dosage, 1-40 minutes later tumbling, ragged breathing, crouching position, occasionally prone position and apathy was observed. After some hours apathy, irregular breathin

Gross pathology:

Animals which died of exposure:
6400 µL/kg bw: Acute dilatation of the heart. Dilation of the stomach (slight) containing thin pulpy contents or bloody ulcerations. Slight diarrhea contents in the intestines or hematised content of the intestines. Yellow gray discoloration of the liver, combined with dilation of the right atrium. General degeneration of the liver. Nephrosis
5000 µL/kg bw: Acute congestive hyperemia. Substance penetration through the stomach as well as Bloody ulcerations., Poor coagulation of the blood. Acute dilatation of the heart. Brightened liver and Toxic liver dystrophy, Toxic nephrosis of the liver (icm Yellow gray discoloration). Hematised content of the intestines. Partly infarctoid blood-fill, partly stain-faced with odematization of the lungs
4500 µL/kg bw: Acute dilatation of the heart. Yellow gray discoloration of the liver. Degeneration of the Kidneys. Total empty stomach-intestinal canal, distended filled with gas. Strong emaciation.

Animals which were necropsied after observation period.
4000 µL/kg bw: Total loss of perirenal adipose tissue. Edema of the for-stomach. Animals largely emaciated.
3200 µL/kg bw: no effects observed.

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 645 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

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 403 (Acute Inhalation Toxicity)

Version / remarks:

May, 1981

Qualifier:

equivalent or similar to guideline

Guideline:

other: Toxic Substances Control Act Test Guidelines (Environmental Protection Agency, September 27, 1985, and revised guidelines 52 FR 19056)

Version / remarks:

May 20, 1987

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

September, 1984

GLP compliance:

yes

Test type:

traditional method

Limit test:

no

Specific details on test material used for the study:

- Name of test substance( as cited in report): Diisopropyl ketone; 2,4-Dimethyl-3-pentanone; DIPK
- Purity: 100 ± 0.00% (mean ± SD)

Species:

rat

Strain:

other: Crl:CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: Males 41 days, Females 52 days
- Weight at study initiation: Males 189 ± 11 g, Females 172 ± 10 g (mean ± SD)
- Housing: Singly housed in multicompartmented stainless steel mesh cages
- Diet: Certified Rodent Diet (Agway Prolab RMH-3000, pellets), ad libitum during non-exposure periods
- Water: ad libitum during non-exposure periods

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 - 23.3 (reported as 70-74 °F)
- Humidity (%): 52 - 56
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

The inhalation exposures were conducted in 420 L stainless steel and glass inhalation chambers at target concentrations of 1250 and 2500 ppm. There was no control group used in this study. The chambers were maintained at pressures of -0.25 and -0.50 inch water (gauge) relative to room air for the low and high-exposure groups, respectively, and at 12 air changes per hour. Male and female rats were singly housed and exposed simultaneously for six hours in the same inhalation chamber.

A vapor was produced by metering the test substance from a reservoir into a glass bead-packed column where it evaporated. The column was supplied with metered, dried, oil-free compressed air. The resultant vapor was directed into the turret of the chamber where it was mixed with filtered, conditioned air. Chamber vapor concentrations were analytically determined 16 times during the exposure by infrared spectroscopy. The samples were taken from a fixed reference position in the inhalation chamber. Chamber temperature and relative humidity were recorded twice per hour. Chamber air flow was set at 84 liters per minute. The nominal chamber concentration was calculated from the mass of chemical consumed and air flow. The concentration of background nongaseous material relative to chamber air and room air was measured twice for each chamber during the exposure to ensure that the exposures were to a vapor and not an aerosol. The concentration of the test substance vapor was measured during a pre-study test, from various positions within the inhalation chamber, to assess the homogeneity of the vapor throughout the chamber.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

6 h

Concentrations:

1462 and 2765 ppm (analytical)
1250 and 2500 ppm (target)
1579 and 4650 ppm (nominal)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Body weights were measured on Days 0, 2, 7, and 14.
Rats visible through chamber windows were observed for clinical signs during exposure. Before and after exposure and on days of body weight measurement, each rat was removed from its cage and examined by a trained technician. Every workday afternoon and on mornings when body weights were not collected, cage side observations were conducted. Observations included, but were not limited to, examination of behavior pattern, motor activity, respiratory patterns, hair, skin, eyes, feces and urine. Animals were checked for mortality on weekends.

- Necropsy of survivors performed: yes
Rats were fasted overnight prior to necropsy on Day 15, anesthetized with C02, and exsanguinated by severing the posterior vena cava.
The following organs were examined during the necropsy: nasal passages, trachea, lungs, heart, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, pancreas, liver, salivary glands, kidneys, urinary bladder, pituitary gland, adrenal glands, thyroid glands, parathyroid glands, thymus, spleen, mesenteric lymph nodes, bone marrow (femoral), brain, testes, epididymides, male accessory sex glands, ovaries, vagina, uterus, and Fallopian tubes.

Statistics:

Mean values were calculated for test substance concentration, chamber temperature, chamber relative humidity, and body weight

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2 765 ppm

Based on:

test mat.

Exp. duration:

6 h

Remarks on result:

other: reversible narcotic effects and lacrimation

Mortality:

No mortality occurred during the course of this study.

Clinical signs:

other: During the exposure, the high-exposure group exhibited severe narcosis and moderate dyspnea, and the low-exposure group exhibited moderate lethargy and minor dyspnea. Immediately after the exposure, all male and female animals from the high exposure group

Body weight:

A very slight body weight loss was observed at both the high-exposure (5/5 males, 3/5 females) and low-exposure levels (2/4 males, 3/5 females) at the Day 2 body weight determination. Subsequently, all animals, except one (Rat 2, low-exposure group), appeared to gain weight normally. Rat 2 exhibited a slight body weight loss at Day 2 apparently due to reduced water intake. This animal was provided with a water bottle, and subsequently recovered. The percent weight gain between Day 0 and 14 for male and female animals were, respectively, +56% and +26% for the high-exposure group and +60% and +22% for the low-exposure group. For the male animals from both exposure levels, this represented a slightly lower weight gain than is commonly seen in rats of this age and strain, although it did not follow a concentration-dependent pattern. Mean terminal body weights for male and female rats from the high- and low-exposure levels were comparable.

Gross pathology:

There were no exposure-related changes detected on gross examination of male or female rats exposed to the test material. No tissue was collected for microscopic examination.

Interpretation of results:

GHS criteria not met

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Principles of method if other than guideline:

Inhalation Risk Test conducted according to a BASF internal testing method. The test demonstrates the toxicity of an atmosphere saturated with vapours of the volatile components of a test substance at the temperature chosen for vapour generation (room temperature). Several groups of usually 3 rats per sex were exposed sequentially to the vapors, generated by bubbling 200 L/h air through a substance column of about 5 cm above a fritted glass disc in a glass cylinder for different time periods (e.g. 3 min, 10 min, 1, 3 or 7 or 8 hours). The exposure time not causing lethality was usually tested twice.
No analytical determination of the atmosphere concentrations was performed. The nominal concentration usually can be calculated as quotient of the amount of test substance weight loss during the exposure, which is given in the raw data, and the amount of air used during the exposure.
The study allows for an estimate of the length of time required to cause severe toxic effects resulting from exposure to an atmosphere saturated with volatile components of the test substance. The exposure time causing 50% lethality (LT50) can be estimated from such a study as described for the LD50. Furthermore, using the nominal concentration, vapor pressure and LT50, in many cases a 4-hour LC50 can be estimated using Haber’s law.

GLP compliance:

no

Test type:

other: Inhalation Risk test

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in report): Diisopropylketon

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: average at 30 min. exposure group: 148 g; average at 1 hour exposure group: 207 g

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

Inhalation of an atmosphere saturated with vapor at 20 °C.
The vapours were generated by bubbling 200 l/h air through a substance column of about 5 cm in a small washing bottle.

Analytical verification of test atmosphere concentrations:

no

Remarks on duration:

30 minutes and 1 hour

Concentrations:

30 minute exposure: 65 mg/L (nominal)
1 hour exposure: 68 mg/L (nominal)

No. of animals per sex per dose:

30 minute exposure: 6
1 hour exposure: 3

Control animals:

yes

Remarks:

3 animals per sex were exposed to air for 30 minutes

Details on study design:

- Duration of observation period following administration: 1 week
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Sex:

male/female

Dose descriptor:

LC0

Effect level:

65 mg/L air

Based on:

test mat.

Exp. duration:

30 min

Remarks on result:

other: 0/12 rats dead after 30 min exposure

Sex:

male/female

Dose descriptor:

other: Mortality

Effect level:

65 mg/L air

Based on:

test mat.

Exp. duration:

1 h

Remarks on result:

other: 4/6 rats dead after 1h exposure

Mortality:

1 hour exposure: 4/6 animals died in the experiment. The surviving animals were without symptoms after 6 days.
30 minutes exposure and control group: no mortality occurred.

Clinical signs:

other: 1 hour exposure: Immediate escape attempts. In the course of the experiment accelerated breathing, narcosis, bloody mucous membrane irritation, stretched hind legs. 30 minute exposure: Immediate escape attempts. During the test anesthesia and bloody muco

Gross pathology:

1 hour exposure: Acute congestion hypertension and acute dilation of the heart (right)
30 minute exposure and control group: No effects observed.

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Based on recalculation via Haber's rule

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

17 000 mg/m³ air

Quality of whole database:

extrapolated LC50 from supporting study. The key study shows absence of mortality at 13125 mg/m3.

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)

GLP compliance:

no

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

- Name of test substance (as cited in report): 2,4-Dimethyl-3-pentone

Species:

rat

Strain:

other: Crl:CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Weight at study initiation: Males 284 - 297 g, Females 227 - 235 g
- Identification: Alll animals were identified by metal ear tags/cage number.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal skin (The hair from the dorsal skin of the rats was removed with an electric clipper).
- Type of wrap if used: Occlusive

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 20 mL/kg bw

Doses:

20 mL/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

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

Statistics:

Method of calculation: Weil method

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 20 mL/kg bw

Based on:

test mat.

Remarks on result:

other: corresponds to 16200 mg/kg bw (based on a relative density of 0.81)

Mortality:

No mortality occurred

Clinical signs:

other: No clinical signs were note during the 14 day observation period.

Gross pathology:

not reported

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

16 200 mg/kg bw

Additional information

ORAL:

In an acute oral toxicity test performed similar to OECD guideline 401 (BASF 1973), a test group consisting of 5 animals/sex was treated by single gavage application with an aqueous solution of the test substance ( 6400, 5000,  4500, 4000, 3200 µL substance/kg applied as a 30 % formulation). The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observations period also were subjected to necropsy. At 6400 and 5000 µL/kg bw all animals died, in most cases within the first week after dosing. At 4500 µL/kg bw only 1 male animal died within the 14 day observation period. One female animal died with 48 hours after dosing and 4/5 died within 7 days after dosing. The last surviving female animal died in the last week of observation (within 14 days). At 4000 and 3200 µl/kg bw, no mortality occurred. The animals showed slight weight loss in the first 7 days, followed by normal growth. Main clinical signs observed were dyspnea, vertigo, prone position, apathy, atonia, and dehydration. Gross pathology revealed, among other, acute dilatation of the heart, dilation of the stomach, brightened liver and toxic liver dystrophy. Necropsy performed on surviving animals showed total loss of perirenal adipose tissue as well as edema of the forestomach. Based on the observed results the LD50 was determined to be 4.5 mL/kg bw or 3645 mg/kg bw, based on the relative density of the substance.

 

INHALATION:

In an OECD Guideline study (403), groups of rats (5/sex/dose) were exposed to 1462 and 2765 ppm of the test substance during a single whole body exposure of 6 hours (Eastman KodaK 1989) . Exposure was followed by a 14 day observation period. In addition to mortality, clinical signs and body weight were recorded. Necropsy was performed on surviving animals. No animals died as a result of the exposure regime. During the exposure, the high-exposure group exhibited severe narcosis and moderate dyspnea, and the low-exposure group exhibited moderate lethargy and minor dyspnea. Immediately after the exposure, all male and female animals from the high exposure group had unkempt facial haircoats and exhibited minor to severe narcosis, hypothermia, and excessive tearing. Fewer high exposure level animals exhibited porphyrin tears (1/5 males), dyspnea (3/5 males, 4/5 females), gasping (2/5 females), rales (3/5 females), or diarrhea (2/5 males). Immediately after the exposure, all male and female animals from the low-exposure group had unkempt facial haircoats and 9 of 10 had minimal to minor lethargy. Exposure-related clinical abnormalities observed on Day 1 consisted of decreased feces for all male and female animals from both exposure groups, unkempt haircoats for all animals from the high-exposure group, and excessive tearing for a single high-exposure male and female. All exposure related clinical abnormalities were resolved by Day 2. Mean terminal body weights for male and female rats from the high- and low-exposure levels were comparable. There were no exposure-related changes detected on gross examination of male or female rats exposed to the test material. No tissue was collected for microscopic examination. Based on these results the LC50 was determined to be > 2765 ppm (ca 13125 mg/m³)

 

In addition an Inhalation Risk Test (BASF 1973) conducted according to a BASF internal testing method was identified. The test demonstrates the toxicity of an atmosphere saturated with vapours of the volatile components of a test substance at the temperature chosen for vapour generation (room temperature). Rats were exposed to the vapours for 30 minutes (12 animals) and for 1 hour (6 animals), generated by bubbling 200 l/h air through a substance column of about 5 cm in a small washing bottle. Saturation concentration was 65 - 68 mg/L air (calculated nominal concentration). Exposure was followed by a 1 week observation period. In addition to mortality, clinical signs were recorded and necropsy performed. The inhalation of a saturated vapor-air mixture for 30 minutes caused no mortality but the exposure for 1 hours let to a mortality of 4/6 animals. Main clinical signs after 1 hour exposure were escape attempts, accelerated breathing, narcosis, bloody mucous membrane irritation, stretched hind legs. The surviving animals were without symptoms after 6 days. Animals exposed for 30 minutes showed gross pathology revealed immediately escape attempts and during the test anesthesia and bloody mucous membrane irritation were observed. The next day the animals were without symptoms. Gross pathological examination of animals exposed for 1 hours showed acute congestion hypertension and acute dilation of the heart (right). No pathological changes were seen in animals exposed for 30 minutes. Based on 4/6 animals that died at the 1 hour exposure group and no mortality in the 30 minute exposure group, it can be calculated using Haber's rule that the LC50 for a period of 4 hour exposure would be in the range of 17 mg/L.

 

DERMAL:

In an acute dermal toxicity test performed similar to OECD guideline 402, 5 male and 5 female rats were dermally exposed to 20 mL/kg bw of the undiluted test substance followed by a 14 day observation period (Eastman Kodak 1988). In addition to mortality, weight gain as well as clinical signs were recorded. Animals were exposed on the dorsal skin of which the hair was removed with an electric clipper. No mortality occurred as a result of exposure and no clinical signs were observed. A normal body weight gain was reported. Based on these results the dermal LD50 was determined to be > 20 mL/kg bw (16200 mg/kg bw).

Justification for classification or non-classification

The extrapolated LC50 for 4h of 17 mg/L (vapour) is between 10 and 20 mg/L. The measured LC50 for the gas form is greater than the saturation concentration of 2765 ppm and this excludes GHS categories of less than 4. Taking the data for gas and vapour into account, the substance has to be classified as Acute Tox Cat 4 (inhalation ) H332: Harmful if inhaled in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Additionally, because of the narcotic effects that occured during and after exposure in an OECD Guideline Study (403) the test substance is considered to be classified for STOT SE Category 3 (H336: May cause drowsiness or dizziness) under Regulation (EC) No. 1272/2008, as amended for the fifth time in Directive EC 944/2013.

The LD50 values for acute dermal and oral single dose toxicity are above the classification threshold of 2000 mg/kg bw given in EC1272/2008. Therefore, the substance is not classified for these endpoints in the European Union.

Based on UN GHS criteria, the substance is assigned acute oral category 5.