Registration Dossier

Administrative data

Description of key information

Skin: Irritating

Eye: corrosive

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:
supporting study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
US department of Transport corrosivity test conducted according to guideline 49 CFR 173.240 (a) (i).
0.5 cc applied to rabbits back, covered with a 1.5 x 1.5 inch gauze pad and 'loosely banded'. Exposure for 4 hours. Examinations at patch removal, 24 and 48 hours.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Male animals, body weight 2-3kg
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
4 hours
Observation period:
48 hours
Number of animals:
6 (male)
Details on study design:
Hair was removed from the dorso-lateral surfaces of the test animals using clippers. Test material (0.5ml) applied to a 1.5 x 1.5 inch, 12 layer gauze pad. The gauze was affixed to the skin of each test animal using two strips of adhesive tape placed over the pad int eh shape of an "X". Immediately following application of the gauze, the animals were immobilized and the entire trunk wrapped with an impervious material (rubber dam) which was held loosely over the test sites for the duration of the 4h exposure period. Following exposure the wrapping and the gauze pads were removed and the test sites washed carefully with warm water. The sites were then examined and evaluated. Examinations were made again at 24 and 48 hours following the initial exposure. Photographs were taken of the sites at the times of examination and at study termination
Irritation parameter:
erythema score
Basis:
mean
Remarks:
out of 6 animals
Time point:
other: 4 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks on result:
probability of moderate irritation
Irritation parameter:
erythema score
Basis:
mean
Remarks:
out of 6 animals
Time point:
24 h
Score:
1.67
Max. score:
3
Reversibility:
not reversible
Remarks on result:
probability of moderate irritation
Irritation parameter:
erythema score
Basis:
mean
Remarks:
out of 6 animals
Time point:
48 h
Score:
1.5
Max. score:
2
Reversibility:
not fully reversible within: 48 hours
Remarks on result:
probability of moderate irritation
Irritation parameter:
edema score
Basis:
mean
Remarks:
out of 6 animals
Time point:
other: 4 h
Score:
0.17
Max. score:
1
Reversibility:
not reversible
Remarks on result:
probability of weak irritation
Irritation parameter:
edema score
Basis:
mean
Remarks:
out of 6 animals
Time point:
24 h
Score:
0.83
Max. score:
1
Reversibility:
not reversible
Remarks on result:
probability of mild irritation
Irritation parameter:
erythema score
Basis:
mean
Remarks:
out of 6 animals
Time point:
48 h
Score:
0.83
Max. score:
2
Reversibility:
not fully reversible within: 48 hours
Remarks on result:
probability of mild irritation
Irritant / corrosive response data:
There was a variation in the degree of response across the 6 animals used. Some showed a moderate inflammation at the test sites whereas others showed evidence of more profound irritation involving edema and deep erythema. Three animals suffered tissue injury when the gauze pads were removed and the skin washed. This was due to the extremely fragile nature of the skin after exposure. Although there was ulceration noted it was therefore considered to be a consequence of the mechanical injury caused during patch removal. The summary of the findings is presented in the table below

Rabbit number

4 hours

24 hours

48 hours

1

Pronounced erythema: slight edema: injury to skin by removal of tape

Decreased erythema; persisting edema; mechanical injury more obvious; discoloration (darkening) of sites

Pronounced edema; localised, moderate erythema; increased discoloration

2

Moderate erythema; no edema or obvious tissue injury from tape removal

Slight edema; wide-spread discoloration

Pronounced edema; slight erythema and discoloration

3

Slight erythema; no edema or tissue injury from tape removal

Continuing erythema; slight edema; slight, localised discoloration

Moderate to severe erythema; slight edema

4

Moderate erythema: some tissue damage from tape

Moderate edema; slight erythema; very slight, localised discoloration

Slight, localised discoloration

5

Moderate erythema

Pronounced erythema; tissue damage from tape removal; “bruised” areas

Moderate to severe erythema

6

Moderate erythema; one area of relatively deep tissue damage from tape removal

Moderate erythema: slight edema; discoloration; obvious mechanical injury from tape removal

Localised discoloration and erythema

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
DMAMP-80 produced clear evidence of irritation, and weakened the skin such that removal of the gauze pads used to administer the test amterial produced tissue damage in 3 of the animals. Based on the absence of treatment related necrosis, the investigator considered DMAMP-80 to be non-corrosive in this assay.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

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:
26 Jan - 16 Feb 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adpoted May 1981
Deviations:
yes
Remarks:
limited documentation
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.6 kg (mean in undiluted and 50% treatment group), 2.5 kg (mean in 25% treatment group)
Vehicle:
water
Controls:
other: the untreated eye served as the control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): 25% dilution, 50% dilution and undiluted (of a 72.03% solution)

VEHICLE
- Concentration (if solution): 75 and 50%
Duration of treatment / exposure:
25 % dilution and undiluted: single application without washing or removal of test substance 20-30 seconds after instillation
50% dilution: single application without washing
Observation period (in vivo):
21 days
Reading time points: 24, 48 and 72 h, and 4, 7, 14 and 21 days
Number of animals or in vitro replicates:
Undiluted: 9 (6 with unwashed and 3 with washed eyes)
50% dilution: 3 (unwashed eyes only)
25% dilution: 9 (6 with unwashed and 3 with washed eyes)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): for 3 rabbits in each of the groups exposed to a 25% solution and undiluted test substance, the eyes were rinsed with 50 mL lukewarm tap water 20 - 30 seconds after instillation. The eyes of the remaining rabbits were not washed.
- Time after start of exposure: 20 - 30 seconds

SCORING SYSTEM: Draize scoring system. The eyes were examined 24, 48 and 72 hours, and 4, 7, 14 and 21 days after treatment.

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: washed eye, undiluted substance
Irritation parameter:
iris score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
1.33
Max. score:
2
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: washed eye, undiluted substance
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
2.76
Max. score:
3
Reversibility:
fully reversible within: 21 days
Remarks on result:
other: washed eye, undiluted substance
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
3.19
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: washed eye, undiluted substance
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
1.34
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: washed eye, 25% dilution
Irritation parameter:
iris score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: washed eye, 25% dilution
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
1.89
Max. score:
3
Reversibility:
fully reversible within: 21 days
Remarks on result:
other: washed eye, 25% dilution
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
out of all 3 animals
Time point:
24/48/72 h
Score:
1.69
Max. score:
4
Reversibility:
fully reversible within: 21 days
Remarks on result:
other: washed eye, 25% dilution
Irritant / corrosive response data:
Undiluted: Immediately after instillation of the test material, the rabbits vocalized, indicating severe eye irritation. At the 24 h time point, the unwashed and washed eyes in all the rabbits showed severe eye irritation with corneal lesions. The severity was only slightly reduced by the 72 h time point. In rabbits with both unwashed and washed eyes the corneal opacity and corneal lesions were still visible by fluorescein treatment on day 7. The corneas were keratinised in all the animals after day 7, a condition which is irreversible. One animal with unwashed and one with washed eyes was sacrificed on day 7 due to the severe eye damage (see Table 1).

The pH of the undiluted liquid is 12.5, which means that the effect of the test substance is most probably due to the high alkalinity. This is also indicated by the severe eye damage that even the 25% dilution caused.

50% dilution: The eyes of the three rabbits showed severe eye irritation from the 24 h time point, with lesions on the cornea. The severity was only slightly reduced by the 72 h time point. The eyes were keratinised after day 14, a condition which is irreversible. One animal was sacrificed on day 14 and one by day 21 due to the severe eye damage.

25% dilution: The eyes of the rabbits in the unwashed and washed group showed severe eye irritation and corneal lesions when examined after 24 hours. The eyes of all the rabbits were keratitised after day 14, with the exception of one animal in the washed eye group, where the effects were almost or completely reversed by day 21. Of the rabbits with unwashed eyes, 4 were sacrificed on day 14 due to the severity of the damage.
Other effects:
There was no effect on body weight.

Table 1. Individual scores for rabbit eyes instilled with undiluted test substance and washed

Rabbit #

 

Time [h]

 

conjunctivae

 

iris

 

cornea

 

redness

swelling

1

 

 

 

 

24

3

4

2

3

48

3*

3.3*

1.3*

2*

72

2.3*

2.6*

1.3*

2*

average

2.77

3.3

1.53

2.33

2

 

 

 

 

24

3

4

1

2

48

3*

3.3*

1.3*

2*

72

2.3*

2.6*

1.3*

2*

average

2.77

3.3

1.2

2

3

 

 

 

 

24

3

3

1

1

48

3*

3.3*

1.3*

2*

72

2.3*

2.6*

1.3*

2*

Average

2.77

2.97

1.2

1.67

* for the 48 and 72-hour reading time points only average scores were reported

 

 

 

 

 

Average score

Time [h]

Conjunctivae

Iris

Cornea

Redness

Swelling

24 h

2.77

3.3

1.53

2.33

48 h

2.77

3.3

1.2

2

72 h

2.77

2.97

1.2

1.67

24+48+72

2.77

3.19

1.31

2

* for the 48 and 72-hour reading time points only an average score of the 3 animals was reported

Interpretation of results:
corrosive
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: Eye corrosion 1, H318
DSD: Xi, R41
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

Four skin irritation/corrosion studies with 2-dimethylamino-2-methyl-1-propanol (DMAMP) are available. DMAMP is a highly alkaline substance; the pH of a 72% solution is 12.5.

In a study performed according to a protocol comparable to OECD 404, rabbits were exposed to a 72.03% solution of DMAMP (Parekh, 1982c). 0.5 mL of the test substance was applied to shaved skin and covered with an occlusive dressing for 24 hours. One rabbit was sacrificed on day 1 due to a broken leg. 24 hours after exposure ended, 6/6 rabbits had severe erythema (grade 4 of 4) and moderate to severe edema. At the 72-hour time point, the erythema grade was unchanged, while the edema had cleared in 5/5 animals. The irritation effects lasted the entire 21-observation period, although signs of healing were noted. DMAMP caused skin irritation under the conditions of this study. 

In a study similar to OECD 404 rabbits were exposed to a 72.03% solution of DMAMP for 4 hours under occlusive conditions (Parekh, 1982d). No individual data was reported. The rabbits had erythema and edema of unknown severity at the 4-hour reading time point, with the erythema persisting until 48 hours after exposure ended. No tissue destruction was noted, indicating that the test substance was not corrosive.

In a US Department of Transport Corrosivity assay, DMAMP-80 (80% purity) was assessed for corrosivity in rabbits (6) according to a guideline similar to the current corrosivity assay. Following a 4 hour (occluded) exposure there were clear signs of irritation (moderate to severe erythem and edema) that persisted in most animals until the end of the 48 hour observation period. Although the substance was highly irritating in this assay there was no evidence of necrosis tissue damage. There was some ulceration observed in 3 animals but this resulted from mechanical damage during removal of the gauze used to adminsiter the test material and is not considered to be chemically mediated corrosivity.

In the 3 available studies for this substance there is clear evidence of irritation that persists to the end o fthe observation period, however there are no signs of corrosivity. As such, even though this substance has a strongly alkaline pH, it does not meet the criteria for classification as corrosive.

Eye irritation/corrosion:

In a study in rabbits (similar to OECD 405), 0.1 mL of a 72.03% solution of DMAMP was instilled undiluted into one eye, after which the eye was either rinsed after 20 -30 seconds or not rinsed at all (Parekh, 1982c). All 9 rabbits exposed to the undiluted substance vocalised immediately after instillation, indicating severe eye irritation. At the 24-hour reading time point, the unwashed and washed eyes in all the rabbits showed severe eye irritation with corneal lesions. The severity was only slightly reduced by the 72-hour reading time point. In rabbits with both unwashed (6/6) and washed (3/3) eyes the corneas were keratinized after day 7, a condition which is irreversible. One animal with unwashed and one with washed eyes was sacrificed on day 7 due to the severity of the eye damage. The pH of the undiluted liquid is 12.5, which means that the effect of the test substance is most probably due to the high alkalinity. DMAMP is considered to have a corrosive effect to eyes under the conditions of the study.

Taking the available data into account and considering the alkaline property of DMAMP, the substance is considered to be corrosive to the eyes.

Justification for selection of skin irritation / corrosion endpoint:

The selected study is the most adequate and reliable study based on overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of eye irritation endpoint:

There is only one study available.

Effects on skin irritation/corrosion: highly irritating

Effects on eye irritation: corrosive

Justification for classification or non-classification

The available data on skin irritation of the test substance meet the criteria for classification as Category 2 (H315) according to Regulation (EC) 1272/2008 and as Xi, R38 according to Directive 67/548/EEC.

The available data on eye irritation of the test substance meet the criteria for classification as Category 1 (H318) according to Regulation (EC) 1272/2008 and as Xi, R41 according to Directive 67/548/EEC.