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Description of key information

A GLP-study according to OECD guideline 401 and several non-GLP studies equivalent or similar to OECD guidelines 401 and 403 are available for diisobutyl ketone (DIBK).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994-11-14 to 1994-11-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): DIBK (Diisobutyl Ketone)
- Physical state: Clear liquid
- Analytical purity: 95.6%
- Lot/batch No.: 02264 00010
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Barriered Animal Breeding Unit, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK
- Age at study initiation: 7 weeks
- Weight at study initiation: Males weighed 241-255g and the females weighed 180-182g
- Fasting period before study: Overnight prior dosing
- Housing: In suspended cages (26.5cm x 50.0cm x 20.7cm). The cages were made of stainless steel, with one solid sheet side and a mesh front, floor, rear and remaining side. The sexes were housed separately with a maximum of five rats per cage.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2
- Humidity (%): 45±15
- Air changes (per hr): 25-30/h
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10mL/kg bw


Doses:
2000 mg/kg bw
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: The animals were observed for signs of systemic toxicity once within 2 hours of dosing and again between 4 and 7 hours after dosing. Subsequent observations were made once daily, or twice daily whenever there were significant signs of toxicity, up to day 15. The animals were weighed on the day before dosing (day -1), the day of dosing (day 1) and days 3, 4, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no mortalities
Clinical signs:
Signs of slight and non-specific systemic toxicity including piloerection, sides pinched in (slight indentation in the sides of the abdomen) and urinary incontinence were observed in female rats. No signs of systemic toxicity were evident in male rats.
Body weight:
All animals gained weight consistently after an initial weight loss due to the overnight fast.
Gross pathology:
Pelvic dilatation of the kidney was observed in one male and pale areas of the lung was observed in one female. These are common spontaneous findings in rats of this age and strain and and are considered not to be treatment related.

The acute oral median lethal dose LD50 of Diisobutyl Ketone (DIBK) was estimated to be in excess of 2000mg/kg to male and female rats. According to DSD and CLP, DIBK has not to be classified.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 of DIBK in rats is greater than 2000 mg/kg. Hence, no classification for acute oral toxicity is required according to EU criteria.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
incomplete experimental data
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Source: Solvents and Coatings Materials, South Charleston, WV
- Name of test material (as cited in study report): Diisobutyl Ketone
- Physical state: Clear non-viscous, liquid; slightly yellow, transparent non-viscous liquid.
- Analytical purity: No data
- Lot/batch No.: 475010-135-500564
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 200-300g
- Fasting period before study: Overnight prior to dosing
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum



Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 16mL/kg bw


Doses:
Volumes of 4, 8 and 16mL/kg bw equivalent to 3200, 6400 and 12800mg/kg bw if the solution is 100% DIBK
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: Daily, weighing at day 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
LD50's are calculated by the moving average method (Thompson, 1947) and are based on a 14 day observation period.
Sex:
male
Dose descriptor:
LD50
Effect level:
6 899 mg/kg bw
Based on:
test mat.
95% CL:
4 669 - 10 224
Remarks on result:
other: Assuming a 100% solution of DIBK
Sex:
female
Dose descriptor:
LD50
Effect level:
5 233 mg/kg bw
Based on:
test mat.
95% CL:
3 800 - 7 205
Remarks on result:
other: Assuming a 100% solution of DIBK
Mortality:
16mL/kg bw: Males: 5 dead out of 5 tested, females: 5/5
8mL/kg bw: Males: 2/5, females: 4/5
4mL/kg bw: Males: 0/5, females 0/5
Clinical signs:
16mL/kg bw: Males: Sluggishness, unsteady gait at 30 min severe sluggishness at 2 hr; prostration, lacrimation, slow respiration, piloerection in 2/5 at 1 day; females: Sluggishness, unsteady gait at 30 min; severe sluggishness at 2 hr; prostration, lacrimation, piloerection, slow respiration in 1/5 at 1 and 2 days.
8mL/kg bw: Males: Sluggishness at 1 hr; unsteady gait at 3 hr; 1 or 2 with prostration, lacrimation, slow respiration at 1 or 2 days; red crust on mouth, nose and eyes at 2 days. Survivors recovered at 2 or 3 days; females: Sluggishness at 1 hr; unsteady gait at 3 hr; 1 or 2 with prostration, slow respiration and lacrimation within 1 day; piloerection at 1 day; sluggishness, piloerection, red crust on mouth, nose and eyes at 2 days. Survivor recovered at 2 days.
4mL/kg bw: Males: Sluggishness, lacrimation in 2 at 1 day. Recovery at 2 days; females: Not noted
Body weight:
Only noted on surving animals from 4 and 8mg/kg bw groups as mean grams between days 0 and 7 and 7 and 14:
8mL/kg bw: males +44 and + 108, females +15 and +50
4mL/kg bw: males +52 and +116, females +27 and +46
Gross pathology:
16mL/kg bw: Males and females: Lungs dark red
8mL/kg bw: Males and females: In victims, lungs dark red. In survivors, nothing remarkable.
4mL/kg bw: Males and females: Nothing remarkable

The LD50 for Diisobutyl Ketone if administered orally is 8.57mL/kg bw for male and 6.5mL/kg bw for female wistar rats. Calculated by the density of 0.805 of Diisobutyl Ketone (relative density to water=1) the LD50 is 6899mg/kg bw for male and 5233mg/kg bw for female wistar rats. However, it can not be excluded that the high dose effects are attributable to the high dosage volumes that had been administered.

According to DSD and CLP Diisobutyl Ketone has not to be classified.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The oral LD50 of DIBK in rats is 6899 mg/kg and 5233 mg/kg in male and female rats, respectively. Hence, no classification for acute oral toxicity is required according to EU criteria.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
5 233 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:
key study
Study period:
1941
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Incomplete experimental data, exposure durations from 1-24h
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 study report): Diisobutyl Ketone
- Physical state: Liquid
- Analytical purity: Usual commercial grade, no further specification
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The apparatus used for producing the continuous flow of vapour was an adaptation of that used by Irish and Adams in their studies on methods for testing the toxicity of vapours. A measured stream of pure air was drawn through a heated tube to which Diisobutyl Ketone was furnished by means of a displacement pump. A loose fitting plunger was lowered into a liquid reservoir by a constant speed electric clock motor. The liquid was displaced and flowed through a side arm into the heated tube through which pure air was being drawn at the desired rate to produce a given concentration of vapour, Prolonged recirculation over a wick saturated with the solvent was utilized to obtain saturated air at room temperature.
- Source and rate of air: The air flow was equivalent to one complete change in 5 to 10 minutes


TEST ATMOSPHERE
- Brief description of analytical method used: During exposures, concentrations were checked with a 50 cm. portable Zeiss interferometer. Each division on the scale was found to be equivalent to 86 ppm of Diisobutyl Ketone. This established a reasonable control, on concentrations
- Samples taken from breathing zone: no


Analytical verification of test atmosphere concentrations:
yes
Remarks:
During exposures, concentrations were checked with a 50 cm portable Zeiss interferometer. Each division on the scale was found to be equivalent to 86 ppm of Diisobutyl Ketone. This established a reasonable control, on concentrations.
Duration of exposure:
>= 1 - <= 24 h
Remarks on duration:
Different durations of exposure were performed combined with the different concentrations
Concentrations:
500, 750, 1000, 1500, 2000 and 2500ppm
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, blood counts
Sex:
not specified
Dose descriptor:
LC50
Effect level:
> 14.5 mg/L air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: According to 14500 mg/m³ air
Mortality:
Deaths occured only in the high dose groups of 2000 and 2500ppm after exposure times of >2h. From 36 tested animals in these groups 4 were found dead. Deaths were usually rapid when they occurred, indicating that the constitutionally weaker animals succumbed promptly
Clinical signs:
other: The symptoms exhibited by the animals during exposure naturally varied from animal to animal but generally were perceived in the following order of development: irritation of the eyes and nose, increased salivation, instability, respiratory difficulty or
Body weight:
No abnormal bodyweight changes in surviving animals were observed
Gross pathology:
A concentration of 750ppm gave rise to only minor lung pathology after a continuous exposure of 24 hours duration.
Other findings:
- Histopathology: Micropathology of the lung, kidney, liver, spleen and adrenal of those animals surviving exposure by 14 days was never severe, with frequency of involvement in that order. A concentration of 750ppm gave rise to only minor lung pathology after a continuous exposure of 24 hours duration.
- Other observations: There is no distinctive alteration in the blood picture except the usual variation seen in blood counts on small animals which is a normal occurrence.

According to guideline OECD 403 the usual exposure time is 4h (240min). All results for this duration are sufficient for determination of an appropriate LC50 and are summarised in table 1:

Table 1: Mortality after 4h exposure to rats

ppm

exposure time

deaths occurred/tested animals

2500

4h

1/6

2000

4h

0/6

The LC50 for Diisobutyl Ketone administered by the inhalative route as vapour to rats is therefore specified as >2500ppm which is equivalent to 14.5 mg/L air and 14500 mg/m³. According to DSD and CLP Diisobutyl Ketone has not to be classified.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute inhalation LC50 of DIBK in rats is greater than 14500 mg/m3 (highest concentration tested). Hence, no calssification for acute inhalation toxicity is required according to EU criteria.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
14 500 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
Study period:
1994-11-14 to 1994-11-29
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
occlusive dressing according to former guideline
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): DIBK (Diisobutyl Ketone)
- Physical state: Clear liquid
- Analytical purity: 95.6%
- Lot/batch No.: 02264 00010
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Barriered Animal Breeding Unit, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK
- Age at study initiation: males 7 weeks, females 9 weeks
- Weight at study initiation: Males weighed 248-268g and the females weighed 232-281g
- Fasting period before study: Overnight prior dosing
- Housing: Individually in suspended cages (26.5cm x 50.0cm x 20.7cm). The cages were made of stainless steel, with one solid sheet side and a mesh front, floor, rear and remaining side.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2
- Humidity (%): 45±15
- Air changes (per hr): 25-30
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 10x5cm on dorso lumbar region
- Type of wrap if used: Each dressing consisted of a gauze patch (approximately 4cm x 6cm x 4-ply) to cover the treated area, which was covered by a patch of plastic film (7.5cm x 5cm) and was held in position using adhesive bandage (approximately 25cm x 5cm). This was secured by two pieces of PVC tape (approximately 2.5cm x 20cm) wrapped around the animal.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, with clean swabs of absorbent cotton wool soaked in clean warm water
- Time after start of exposure: 24h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000mg/kg bw
- Concentration (if solution): 95.6%


Duration of exposure:
24h
Doses:
2000 mg/kg bw
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: The animals were observed for signs of systemic toxicity once between one and four hours after application on the day of dosing and then once daily for systemic toxicity and skin irritation, up to day 15. The animals were weighed immediately before application of the test sample (day 1), and on days 3, 4, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no mortalities
Clinical signs:
There were no signs of systemic toxicity. Signs of slight skin irritation were observed in all animals including erythema, oedema and desquamation. All signs of irritation had completely regressed by day 8.
Body weight:
The majority of animals lost weight initially but all animals had exceeded their initial bodyweight by the end of the study.
Gross pathology:
Pelvic dilatation of the kidney was observed in one male and a reddened cervical lymph node was observed in one female. These are common spontaneous findings in rats of this age and strain and are considered not to be treatment related.

The acute dermal median lethal dose LD50 of Diisobutyl Ketone (DIBK) was in excess of 2000 mg/kg to male and female rats. DIBK has therefore not to be classified according to DSD and CLP.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal LD50 of DIBK in rats is greater than 2000 mg/kg. Hence, no classification for acute dermal toxicity is required according to EU criteria.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

The oral LD50 values for DIBK in experiments in rats ranges from 3200 to 6899 mg/kg and greater than 3200 mg/kg in mice. The dermal LD50 values ranged from greater than 2000 to greater than 16100 mg/kg in rats, 4556 to 10868 mg/kg in rabbits and greater than 16 mg/kg in guinea pigs. As the rat is the relevant species for classification and labeling criteria, the LD50 value from the rat study is being taken as the key value. The inhalation LC50 value for DIBK in rats and guinea pigs was greater than 11500 mg/m3 after 4 hours of exposure.

Justification for classification or non-classification

LD50 values for oral and dermal route are greater than 2000 mg/kg/bw and LC50 values are greater than 20 mg/l. According to the EU criteria for classification and labeling, diisobutyl ketone is not classified for acute toxicity for any route of exposure.