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Administrative data

Description of key information

MIPA was found corrosive to the rabbit skin under occlusive conditions. Dermal application for 5 or 15 min caused bleeding, while a 20-hour exposure induced severe edema, erythema and necrosis.
Single application of undiluted MIPA to the rabbit eye caused corrosion with severe corneal opacity, severe erythema and iritis.
Inhalation of 230 - 1005 mg/m3 MIPA for 3 hours induced sensory and little pulmonary irritation in mice.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06. Oct 1965 - 14. Oct 1965
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
BASF-Test: Animals were treated for 1, 5, 15 min and 20 hours using occlusive conditions. An application site of 2.5x2.5 cm was covered with the liquid test substance. After the application time (1, 5 and 15 min) the skin was washed with Lutrol (50%). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 hours and at the end of the observation period (8 days). For a final evaluation, the findings after 48 h and 72 h from the raw data were taken into account.
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: male: 2.76 kg (mean), female: 3.01 kg (mean)
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
no
Duration of treatment / exposure:
1, 5, 15 min and 20 h.
Observation period:
8 days
Number of animals:
1 min: 4
5 and 15 min: 6
20 h: 2
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): 1x Lutrol and 1x 50% Lutrol
- Time after start of exposure: Immediately after 1, 5 and 15 min exposure.
Irritation parameter:
erythema score
Remarks:
1 min exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
erythema score
Remarks:
5 min exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
1.1
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: bleeding in 3/6 animals
Irritation parameter:
erythema score
Remarks:
15 min exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
1.4
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: bleeding in 4/6 animals, anemic necrosis at the end of the observation period in 1/6 animal
Irritation parameter:
erythema score
Remarks:
20 h exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: grey-blackish, relocatable necrosis beyond the application area
Irritation parameter:
edema score
Remarks:
1 min exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
0
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Irritation parameter:
edema score
Remarks:
5 min exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
0.7
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: bleeding in 3/6 animals
Irritation parameter:
edema score
Remarks:
15 min exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
0.6
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: bleeding in 4/6 animals, anemic necrosis at the end of the observation period in 1/6 animal
Irritation parameter:
edema score
Remarks:
20 h exposure
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
2.5
Max. score:
4
Reversibility:
not fully reversible within: 8 days
Remarks on result:
other: grey-blackish, relocatable necrosis beyond the application area
Irritant / corrosive response data:
At the end of the observation period of 8 days scale and crust formation was noted and in one animal of the 15 min application group anemic necrosis was observed.

Mean erythema score after 24, 48 and 72 h (animal 1/2/3/4/5/6):

Exposure time  24 h  48 h  72 h  mean        
 1 min  2/0/0/0  2/0/0/0  2/0/-/- 2/0/0/0        
 5 min  2/2/1/1/1/0 2/2/1/1/1/0 -/2/1/1/0/-  2/2/1/1/0.6/0        
 15 min  2/2/1/2/2/0  2/2/1/2/2/0  -/2/1/2/0/- 2/2/1/2/1.3/0        
 20 h  3/0  3/0  3/0  3/0        

Mean edema score after 24, 48 and 72 h (animal 1/2/3/4/5/6):

 Exposure time  24 h  48 h  72 h  mean        
 1 min  0/0/0/0  0/0/0/0  0/0/0/0  0/0/0/0        
 5 min  2/0/0/0/2/0  2/0/0/0/2/0  2/0/0/0/2/0  2/0/0/0/2/0        
 15 min  2/2/0/0/0/0  2/2/0/0/0/0  2/0/0/0/0/0  2/1.3/0/0/0/0        
 20 h  3/3  3/3  0/3  2/3        

The test substance caused bleeding after a 5 minute (3/6) or 15 min (4/6) application. At the end of the observation period of 8 days scale and crust formation was noted and in one animal of the 15 min application group anemic necrosis was observed.

The 20 h application led to severe edema and erythema and caused grey-blackish, relocatable necrosis beyond the application area.

The original BASF grading was converted into the numerical grading according the OECD Draize system (according to Grundler, 1983).

Interpretation of results:
Category 1B (corrosive) based on GHS criteria
Conclusions:
During the application of the test substance, a 5 minute application period resulted into severe edema and erythema and caused grey-blackish, relocatable necrosis beyond the application. Besides bleeding was observed for 3/6 animals.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06. Oct 1965 - 14. Oct 1965
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
BASF-Test: 50 µL of the test substance were applied to the conjunctival sac of one eye in 2 animals. The animals were observed after 10 min, 1 and 3h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405. The report describes findings after 1 and 24 hours and at the end of the observation period. For final evaluation, the findings after 48 and 72 hours from the raw data were taken into account.
GLP compliance:
no
Specific details on test material used for the study:
- Analytical purity: 98 %
Species:
rabbit
Strain:
Vienna White
Vehicle:
unchanged (no vehicle)
Controls:
other: The adjacent eye served as saline control.
Amount / concentration applied:
TEST MATERIAL
- Amount applied (volume or weight with unit): 50µl
Duration of treatment / exposure:
single application
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
2
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: 72 h reading is missing
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 h - 48 h - 72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: 72 h reading is missing
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24 h - 48 h - 72 h
Score:
2
Max. score:
2
Reversibility:
not reversible
Remarks on result:
other: 72 h reading is missing
Irritant / corrosive response data:
The detailed findings of the study are given in table 1 as converted gradings from BASF internal into OECD Draize system gradings.

Table 1: Findings of two animals: animal 1/animal 2

 Time      Opacity Iritis Erythema Chemosis                   
 1 h    2/2 0/0 1/1  0/0                  
 24 h    3/3  2/0  3/3  0/0                  
 48 h    3/3  2/0  3/3 0/0                   
 72 h    -/-  -/-  -/-  -/-                  
 8 d    3/3  2/0  3/3  0/0                  

The original readings at 72 h are missing. The original BASF grading was converted into the numerical grading according the OECD Draize system.

Mean values over 24 h and 48 h; The 72 h reading is missing:

Animal1: Opacity: 3; Iritis: 2; Erythema: 3;

Animal2: Opacity: 3; Iritis: 0; Erythema: 3;

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
The application of the test substance caused corrosion to the exposed eyes predominantly expressed by severe corneal opacity, severe erythema and iritis. After 48 h crusty eyelids, suppuration and staphyloma were noted. Severe corneal opacity and staphyloma are considered to be irreversible effects to ophthalmic tissue.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Additional information

Skin irritation/corrosion

MIPA was applied to the skin of Vienna White rabbits for 1, 5, 15 min or 20 hours (using 4, 6, 6, or 2 animals, respectively) under occlusive conditions and observed for 8 days. Application caused bleeding after a 5 minute (3 animals) or 15 minute (4 aminals) exposure. At the end of the 8-day observation period scale and crust formation was noted and in one animal of the 15 min application group anemic necrosis was observed. The 20 h application led to severe edema and erythema and caused grey-blackish, relocatable necrosis beyond the application area.

In a human case study, workers in the milling department of a titanium dioxide production plant were exposed to MIPA during maintenance operations or when leaks occured (Hervin and Lucas, 1973, 1974). 15 randomly selected individuals were questioned regarding their general health. Five instances of primary irritant contact dermatitis due to direct skin exposure to MIPA were identified. Another individual also noted upper respiratory tract and eye irritation due to this substance. MIPA represented a definite cutaneous hazard upon direct contact with the skin.

Eye irritation/Serious eye damage

MIPA was applied to conjunctival sac of the eyes of 2 Vienna White rabbits. Animals were observed 10 min, 1 and 3 hours, and up to 8 days after the treatment. The application caused corrosion (irreversible), predominantly expressed by severe corneal opacity, severe erythema and iritis. After 48 hours crusty eyelids, suppuration and staphyloma were noted. MIPA was judged corrosive to the eyes.

Respiratory irritation

In a study on respiratory irritation, mice were exposed to aerosol concentrations of 230 to 1005 mg/m3 MIPA (Detwiler-Okabayashi, 1996, see IUCLID section 7.2.2). The observed parameters for respiratory irritation were the breathing frequency. The 3-hour exposure caused sensory irritation (immediate onset) and little pulmonary irritation (delayed onset). No mortality was observed. Post-exposure recovery of the breathing frequency was moderate to good. The RD50 (concentration capable of evoking a 50% decrease in mean breathing frequency; -/+ 95% CI) was calculated to be 400 (277 - 593) mg/m3. No further information, e.g. clinical chemistry, necropsy, organ weights or histopathology are available.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008 , as amended for the tenth time in Regulation (EU) No 2017/776. As a result the substance needs to be classified as corrosive to the skin (Cat. 1B, H314) and eyes (Cat. 1, H318) under Regulation (EC) No. 1272/2008.