Registration Dossier

Toxicological information

Eye irritation

Currently viewing:

Administrative data

Endpoint:
eye irritation: in vivo
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
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reference
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 for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
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 or test system 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.
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
incomplete experimental data
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
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:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 200-300g




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: sealed animal chamber
- Exposure chamber volume: 120 liter for static and 9 liter for dynamic conditions
- Source and rate of air: 2.5L/min for dynamic conditions

TEST ATMOSPHERE
- Samples taken from breathing zone: no




Analytical verification of test atmosphere concentrations:
not specified
Duration of exposure:
6 h
Remarks on duration:
static and dynamic conditions
Concentrations:
Saturated vapour, oxygen is added, as needed, for static exposures to maintain a chamber oxygen content of approximately 20%.
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, gross pathology
Sex:
male/female
Dose descriptor:
LC50
Effect level:
other: saturated vapour
Based on:
test mat.
Exp. duration:
6 h
Remarks on result:
other: Concentration and temperature not further specified
Mortality:
males: 0/5
females: 0/5
Clinical signs:
other: Ataxia within 2 hr; labored breathing within 3 hr. On removal, hypoactivity, negative toe and tail pinch reflex and slow surface righting reflex. Recovery at one day.
Body weight:
From day 0 to 7: Males: +40g, females +7g
From day 7 to 14: Males: +76g, females +19g
Gross pathology:
Nothing remarkable

Rats exposed to substantially saturated vapor had hypoactivity, ataxia, impaired reflexes and labored breathing. None of the 5 males or 5 females died from the 6-hr exposure. All animals recovered within one day and no remarkable gross pathologic findings were observed. Classification is not feasible due to missing information on concentration of test material.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No mortality was observed in male and female rats after 6 hours of exposure to saturated vapor of DIBK. Hence, no classification for acute inhalation toxicity is required according to EU criteria.
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
purity of test substance not specified, occlusive dressing according to former guideline
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:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2-3kg
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
Type of coverage:
occlusive
Vehicle:
not specified
Details on dermal exposure:
TEST SITE
- Area of exposure: Trunk
- Type of wrap if used: Impervious sheeting, not further specified
- Animals are immobilized

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4, 8, 16mL/kg bw
- Concentration (if solution): Sample dosed as received
Duration of exposure:
24h
Doses:
Volumes of 4, 8 and 16mL/kg bw which would be equivalent to 3200, 6400 and 12800mg/kg bw if the solution was 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:
4 556 mg/kg bw
95% CL:
3 276 - 6 327
Remarks on result:
other: Assuming a solution of 100% DIBK
Sex:
female
Dose descriptor:
LD50
Effect level:
10 868 mg/kg bw
95% CL:
4 331 - 27 048
Remarks on result:
other: Assuming a solution of 100% DIBK
Mortality:
16mL/kg bw: Males: 5 deaths out of 5 tested, females: 3/5
8mL/kg bw: Males: 2/5, females: 1/5
4mL/kg bw: Males: 0/5, females: 0/5
Clinical signs:
16mL/kg bw: Males: Immediate signs of discomfort (intense squirming and struggling); sluggishness and unsteady gait in 1/5, prostration in 1/5 at 1 day; females: Immediate signs of discomfort; sluggishness, unsteady gait in 2/5 at 1 day, survivors recovered at 6 days.
8mL/kg bw: Males: Sluggishness, unsteady gait at 1 day. Recovery of survivor at 6 days. Emaciation in 1/5 at 7 days; females: Immediate signs of discomfort; sluggishness, unsteady gait in 2/5 at 1 day. Survivors recovered at 4 days.
4mL/kg bw: Males: Sluggishness, unsteady gait in 2/5 at 1 day; prostration in 1/5 at 2 days. Survivor recovered at 3 days; females: Immediate signs of discomfort; sluggishness in 3/5 at 1 day. Recovery at 3 to 6 days.
Body weight:
Mean body weight changes of the survivors from day 0 to day 7: 16mL/kg bw: Males: no survivors, females: -180g; 8mL/kg bw: Males: -210, females: -76g; 4mL/kg bw: Males: -31, females: -259;
Mean bodyweight changes of the survivors from day 7 to day 14: 16mL/kg bw: Males: no survivors, females: -70g; 8mL/kg bw: Males: -41, females: +135g; 4mL/kg bw: Males: +61, females: -96
Gross pathology:
16mL/kg bw: Males: Cecum of 2/5 filled with paste-like fecal materials; urinary bladder of 1/5 filled with dark red fluid; females: Nothing remarkable.
8mL/kg bw: Males: In victims, lungs with dark red patches; thoracic cavity of 1/5 filled with caseous material. In one victim, trachea with dark red patches (mucosal surface); liver mottled light brown to red. In survivor, nothing remarkable; females: In victims, cecum filled with paste-like material. In survivors, livers with multiple cream-colored foci.
4mL/kg bw: Males: In victims, intestines of 2/5 filled with fluid to firm fecal material. In survivor, nothing remarkable; females: Livers with multiple cream-colored foci.

The percutaneous LD50 for male rabbits was 3.36 mL/kg. For females, diisobutyl ketone was considerably less toxic, with a calculated LD50 of 13.5 mL/kg. The percutaneous test for males was repeated and the second LD50 was 8.57 mL/kg. Combining the mortality data from both sets of male rabbits gave an LD50 of 5.66 mL/kg. Calculated by the density of 0.805 (relative density to water=1) the LD50 is 4556mg/kg bw for male and 10868mg/kg bw for female wistar rats.

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 dermal LD50 of DIBK is 4556 and 10868 mg/kg in male and female rabbits, respectively. Hence, no classification for acute dermal toxicity is required according to EU criteria.
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
occlusive dressing according to former guidelines, concentration not specified
GLP compliance:
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:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum



Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5mL
- Concentration (if solution): As supplied


Duration of treatment / exposure:
4h
Observation period:
14 days
Number of animals:
6
Details on study design:
TEST SITE
- Type of wrap if used: The dose is applied to the clipped, intact skin under a gauze patch and is loosely covered with impervious sheeting.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Excess sample is removed after contact.
- Time after start of exposure: 4h


SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of all 6 animals
Time point:
24/48/72 h
Score:
1.89
Max. score:
4
Reversibility:
fully reversible within: 10 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: male
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: male
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: male
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: female
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 10 days
Remarks on result:
other: female
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: female
Irritation parameter:
edema score
Basis:
mean
Remarks:
of all 6 animals
Time point:
24/48/72 h
Score:
0.44
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 72h
Remarks on result:
other: male
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
other: male
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: male
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: female
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
other: female
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
other: female
Irritant / corrosive response data:
Minor desquamation developed by 7 days and persisted to the end of the observation period of 14 days in 4 of 6 animals.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results of the study, DIBK was concluded as not irritating to occluded rabbit skin. Mean scores for erythema and edema calculated over all animals were 1.89 and 0.44, respectively.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Concentration not specified, test conditions insufficient described
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
No data

Test system

Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.005, 0.01 and 0.1mL
- Concentration (if solution): As supplied


Duration of treatment / exposure:
7 days without washout
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
6/volume
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: No


SCORING SYSTEM: Draize


TOOL USED TO ASSESS SCORE: 2% fluorescein

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
other: 0.1mL
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: no effects
Remarks on result:
other: 0.1mL
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: 0.1mL
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0.4
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: 0.1mL
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
other: 0.01mL
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: no effects
Remarks on result:
other: 0.01mL
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
other: no effects
Remarks on result:
other: 0.01mL
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects
Remarks on result:
other: 0.01mL
Irritant / corrosive response data:
Scores for 0.005mL were not reported due to missing effects at 0.01mL

Any other information on results incl. tables

Diisobutyl Ketone (DIBK) showed only minor irritation in rabbit eyes after instillation of 0.1mL test material that was fully reversible within 7 days. Diisobutyl Ketone has not to be classified according to DSD and CLP. However the concentration of the received test substance had not been reported.

Applicant's summary and conclusion

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The mean scores for cornea, iris, conjunctivae and chemosis over all animals at 24, 48 and 72 hours were below 0.5. Hence, no classification according to DSD and CLP is required for diisobutyl ketone.