Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Skin irritation: slight (after 2-hr) to moderate (after 24-hr) in rabbits; observation time too short for complete recovery; considered as skin irritant
Eye irritation: initially mild to moderate in rabbits, reversible; bleow CLP criteria; data do not confirm Annex VI classification as eye irritant
Respiratory irritation: irritating, produced lesions in the nasal cavity; considered as respiratory irritant

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
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
Remarks:
Exposure period only 2 hours however under occlussive condisitions. The study was performed in accordance with a recognized scientific procedure for analyzing the primary skin irritation of a test material in experimental animals. The study meets acceptable scientific standards and provides sufficient information to support the conclusion that the test material is a mildly irritating substance to the skin of rabbits.
Qualifier:
according to guideline
Guideline:
other: "Appraisal of the safety of chemicals in foods, drugs and cosmetics", by the staff of the Devisoion of Pharmacology, FDA, Hautgiftigkeit nach Draize (1959)
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
occlusive
Preparation of test site:
other: shaved and shaved/scarified
Controls:
other: two untreated areas (shaved and shaved/scarified)  were used as the control
Amount / concentration applied:
0.5 mL/undiluted
Duration of treatment / exposure:
2 hour(s)
Observation period:
72 h
Number of animals:
6
Details on study design:
Application: 2 hours, occlusive Six New Zealand White rabbits were assigned to study.  In order to investigate the reproducibility of the effects, each rabbit had two separate dose sites (shaved and  shaved/scarified), which were treated with 0.5 ml of undiluted test material.  In addition, two untreated areas (shaved and shaved/scarified)  were used as the control.  Only reactions which were different from those of the control were evaluated as positive reactions. For each treated  dose site, 0.5 ml of undiluted test material was soaked onto a gauze patch (approx. 6 cm²/1 in²) which was held in place with adhesive tape on  the shaved and shaved/scarified skin of the test animals.  The animals were fixed in a holding device and their bodies were wrapped in a  rubberised cloth for 2 hours.  After this time dressing and adhesive tape were removed and the local reactions were examined.  The test sites also  were examined 24 and 72 hours after application.  The test result is the average of the scores of the 24- and 72-hour examinations.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Remarks on result:
other: occlusive, exposure time 2h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean). Mean 24 + 72 h, 48 h was not evaluated.
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.083
Max. score:
4
Remarks on result:
other: occlusive, exposure time 2h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean). Mean 24 + 72 h, 48 h was not evaluated.
Irritation parameter:
erythema score
Basis:
animal: #1, #3, #4, #6
Time point:
other: mean 24+72 h
Score:
0
Max. score:
4
Remarks on result:
other: occlusive, exposure time 2h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
erythema score
Basis:
animal: #2, #5
Time point:
other: mean 24+72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 2h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
edema score
Basis:
animal: #1, #3, #4, #5, #6
Time point:
other: mean 24+72 h
Score:
0
Max. score:
4
Remarks on result:
other: occlusive, exposure time 2h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean 24+72 h
Score:
0.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 2h, observation time 72 h, intact skin, reevaluated acc. CLP criteria

Shaved skin: Under the conditions described, 24 hours after application 2 animals showed slight erythema and 1 animal slight edema.  72 hours after  

application slight edema was observed in one animal and slight edema in one animal.     

As the test used 6 animals, the data were reevaluated according to CLP und DSD criteria for the shaved intact skin.

Interpretation of results:
slightly irritating
Conclusions:
Classification: not irritating
Executive summary:

In a primary dermal irritation study according to “Appraisal of the safety of chemicals in foods, drugs and cosmetics” by the staff of the Devision of Pharmacology, FDA, Hautgiftigkeit nach Draize (1959), 6 young adult New Zealand White rabbits were dermally exposed to 0.5 mL of EMA for 2 hours to 2.5 cm x 2.5 cm body surface area of the shaved and shaved/scarified skin. Animals then were observed for 3 days. Irritation was scored by the Draize method. This scoring system is similar to OECD guideline 404.

Only animals with the shaved intact skin were evaluated for C&L purposes.

Under the conditions described, 24 hours after application 2 animals showed slight erythema. 72 hours after application slight erythema was still observed in two animals and slight edema in one animal.

As the test used 6 animals, the data were reevaluated according to CLP und DSD criteria for the shaved intact skin.

The observation time did not extend beyond 72 hours, even though a slight skin response was still present at that time in 2/6 animals. Therefore, the full reversibility of the effects cannot be proved. However all irritation scores are at most 1.

Therefore, a full reversibility in all animals seems to be likely if the observation period had been extended to the period stipulated in the international guidelines.

In this test, the test substance showed a very slight irritating activity.

Study performance does not comply with requirements of the relevant recent EU and OECD guidelines, were semi-occlusive dressing, an exposure period of 4 hours, treatment of only intact skin and a recovery period of up to 14 days is stipulated. Study is therefore of limited adequacy for C&L purposes due to reduced exposure time and too short recovery period.

 

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Remarks:
Study meets minimum scientific standards for a dermal irritation study and provides sufficient information regarding the irritation potential of the test substance. Exposure longer (24 h) than current guideline standard (4 h).
Qualifier:
according to guideline
Guideline:
other: Federal Hazardous Substances Labelling Act Regulations, Section 191.11, Federal Register: 29, 13009 (1964)
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
occlusive
Preparation of test site:
other: half abraded/half intact
Vehicle:
not specified
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
24 hour(s)
Observation period:
up to 72 hrs
Number of animals:
6
Details on study design:
Six NZ White rabbits were restrained in stocks and the fur removed by  clipping.Half of the exposed area was abraded and the other half  remained intact. 0.5 ml (vol) of test compound was applied to the shaved  intact and abraded skin sites and covered with surgical gauze. The area  was then wrapped with impervious tape measuring 2.5 x 2.5 cm² and a stockinette sleeve.  Test  material remained in contact for 24 hrs and then removed.  Irritation  scores were determined at 24 and 72 hours after patch removal.
Irritation parameter:
edema score
Basis:
mean
Time point:
other: mean 24+72 h
Score:
1.67
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: mean 24+72 h
Score:
1.34
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).
Irritation parameter:
erythema score
Basis:
animal: #1, #5
Time point:
other: mean 24+72 h
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
erythema score
Basis:
animal: #2,#4
Time point:
other: mean 24+72 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
erythema score
Basis:
animal: #3, #6
Time point:
other: mean 24+72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
edema score
Basis:
animal: #1, #5
Time point:
other: mean 24+72 h
Score:
0.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
edema score
Basis:
animal #6
Time point:
other: mean 24+72 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean 24+72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
edema score
Basis:
animal #4
Time point:
other: mean 24+72 h
Score:
2.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean 24+72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. CLP criteria
Irritant / corrosive response data:
Either slight or well defined erythema and from barely perceptible to  moderate edema of the skin at 24 hrs. 
Evidence of irritation persisted  at 72 hrs.

Reevaluated according CLP criteria

Shaved skin:

 

Animal Nr.

Erythema

24 h

Erythema

48 h

Erythema

72h

Mean

Erythema

Edema

24 h

Edema

48 h

Edema

72 h

Mean

Edema

1

1

-

0

0.5

1

-

0

0.5

2

2

-

1

1.5

2

-

2

2

3

2

-

2

2

3

-

3

3

4

2

-

1

1.5

2

-

3

2.50

5

1

-

0

0.5

1

-

0

0.50

6

2

-

2

2

1

-

2

1.5

 

Comparison with CLP criteria:

Remark: Exposure time was higher than 4 hours, observation time only 72 hours.

Two scores were > 2.3 but observation time too short. The highest mean erythema score is 2 for 3/6 animals. The highest edema score is 3 for 1/6 animals. The observation time was too short to demonstrate reversibility.

 

Shaved and scarifized skin (not used for evaluation):

 

 

Animal Nr.

Erythema

24 h

Erythema

48 h

Erythema

72h

Mean

Erythema

Edema

24 h

Edema

48 h

Edema

72 h

Mean

Edema

1

1

-

0

0.5

1

-

0

0.5

2

2

-

1

1.5

2

-

2

2

3

2

-

2

2

3

-

3

3

4

2

-

1

1.5

2

-

3

2.50

5

1

-

1

1

1

-

1

1

6

2

-

2

2

1

-

2

1.5

 

Reevaluated acc. DSD criteria

 

2 h Exposure, shaved skin, occlusive

Erythema

Edema

24h

72h

24h

72h

Animal 1

1

0

1

0

Animal 2

2

1

2

2

Animal 3

2

2

3

3

Animal 4

2

1

2

3

Animal 5

1

0

1

0

Animal 6

2

2

1

2

Mean 

1.67

1

1.67

1.67

Overall mean 

1.34

1.67

Erythema

Edema

Interpretation of results:
moderately irritating
Conclusions:
Classification: irritating
Executive summary:

In a primary dermal irritation study according to “Federal Hazardous Substances Labelling Act Regulations, Section 191.11, Federal Register: 29, 13009 (1964), 6 young adult New Zealand White rabbits were dermally exposed to 0.5 mL of EMA for 24 hours to 2.5x 2.5 cm body surface area of the shaved/scarified skin. Animals then were observed for 3 days. Irritation was scored by the Draize method. This scoring system is similar to OECD guideline 404.

Only animals with the shaved intact skin were evaluated for C&L purposes.

24 h after application 2 animals showed very slight (score1) and 4 animals well defined (score 2) signs of erythema and 3 animals very slight (score 1), 2 animals slight (score 2) and 1 animal moderate (score 3) edema. 72 h after application 2 animals showed no erythema (score 0), 2 animals very slight (score 1) and 2 animals well defined erythema (score 2). No edema were observed after 72 h in 2 animals, slight edema (score 2) in 2 animals and moderate (score 3) in 2 animals. Acc. CLP criteria in 2/6 animals mean edema scores (24 +72h) were > 2.3. As observation time was only 72 h and reversibility could not be observed EMA is considerd as irriating to skin.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Remarks:
DATA QUALITY: Study meets minimum scientific standards for an eye irritation study and provides sufficient information regarding the irritation potential of the test substance. However, there was a limited description of the substance (i.e. purity, CAS#, etc.) Thus, the results are regarded as reliable with restriction.
Qualifier:
according to guideline
Guideline:
other: Federal Hazardous Substances Labelling Act Regulations, Section 191.12, Federal Register: 29, 13009 (1964)
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
Amount applied: 0.1 ml
Duration of treatment / exposure:
72 hour(s)
Number of animals or in vitro replicates:
6
Details on study design:
Six female NZ White rabbits, weighing 2-2.5 kg,  were administered 0.1 ml  (vol) of test compound into the everted lower lid of one eye of each  rabbit; eyelids were closed and held shut for 1 second. Prior to  administration the eyes of each rabbit were examined.  Eyes remained  unwashed. Eyes scored at 24, 48 and 72 hrs after administration with the  aid of an ophthalmoscope and Fluorescein sodium. The eyes were unwashed.
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #4, #5, #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal: #2, #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #5
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #4
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: scores are showing tendency in reversibility
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: #1, #3
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: scores are showing tendency in reversibility
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.66
Max. score:
3
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: scores are showing tendency in reversibility
Irritation parameter:
chemosis score
Basis:
animal: #4, 5, 6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: scores are showing tendency in reversibility
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: scores are showing tendency in reversibility
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.66
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: scores are showing tendency in reversibility
Irritant / corrosive response data:
Conjunctival irritation, redness (max. grade 3 in 3/6 rabbits) and  chemosis (max. grade 3 in 2/6 rabbits) at 24 hr. Irritation (redness and  chemosis), grade 3, was still present at 48 hr in 3/6 rabbits. At 72 hrs  the irritation (redness) was grade 2 in 1/6,  grade 1 in 3/6; chemosis  was grade 2 in 1/6, grade 1 in 1/6 and 0 in 4/6 rabbits. Slight  irritation of the cornea was observed after 24 h in 2/6 animals which was  reversible after 48 h. There was no involvement of the iris.

Animal No.

Corneal opacity/Hornhauttrübung[Scores]

 

Mean Draize score

after 24 h

after 48 h

after 72 h

 

1)

0

0

0

0,0

2)

1

0

0

0,33

3)

1

0

0

0,33

4)

0

0

0

0,0

5)

0

0

0

0,0

6)

0

0

0

0,0

 

0,33

0,0

0,0

0,11

 

 

 

 

 

Animal No.

Iritis/Regenbogenhautentzündung[Scores]

 

Mean Draize score

after 24 h

after 48 h

after 72 h

 

1)

0

0

0

0

2)

0

0

0

0,0

3)

0

0

0

0,0

4)

0

0

0

0,0

5)

0

0

0

0,0

6)

0

0

0

0,0

 

0,0

0,0

0,0

0,0

 

 

 

 

 

Animal No.

Conjunctiva redness (erythem) /Bindehautrötung[Scores]

 

Mean Draize score

after 24 h

after 48 h

after 72 h

 

1)

3

3

1

2,33

2)

3

3

2

2,67

3)

3

3

1

2,33

4)

2

1

1

1,33

5)

1

0

0

0,33

6)

2

1

0

1

 

2,33

1,83

0,83

1,67

Animal No.

Conjunctiva chemosis /Bindehautödem[Scores]

 

Mean Draize score

after 24 h

after 48 h

after 72 h

 

1)

3

2

1

2

2)

3

2

2

2,33

3)

2

2

0

1,33

4)

0

0

0

0,0

5)

0

0

0

0,0

6)

1

0

0

0,33

 

1,5

1

0,5

1
Interpretation of results:
slightly irritating
Conclusions:
Classification: not irritating
Executive summary:

In an occular irritation test acc. the federal Hazardous Substances and Labelling Act Regulations, Section 191.12 published in the Federal Register - 29 F.R. 13009, 1964. Ethyl methacrylate (0.1 ml) was placed in the conjunctival sac of the right eye of six New Zealand White rabbits. The lids were then gently held together for one second.   The test eyes were not washed out following the instillation.   The left eye remained untreated for control.  The eyes were examined at 1, 24, 48 and 72 hours. Eye irritation was scored for signs of corneal damage (density, area), iris reaction and lesions of the conjunctivae (erythema, chemosis). Additionally, the cornea was examined with the aid of fluorescein after recording the observations at 24 hours. No observation after 72 hrs. Scores were reevaluated acc. CLP criteria. Highest mean cornea score (24+48+72 h) was 0.33 in 2/6 animals, no animal showed iritis, 3/6 animals showed conjunctival erythema > 2 and 2/6 animals cunjunctival chemosis > 2. Scores showed clear tendency in rapid reversibility but during the short observation time (72 h) full reversibility could not be observed in all animals (scores in 2/6 animals were fully reversible).

Endpoint:
eye irritation: in vivo
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
Remarks:
Study was performed in accordance with a recognized scientific procedure for analyzing the eye irritation of a test material in experimental animals. The study meets acceptable scientific standards and provides sufficient information to support the conclusion that the test material is a mildly irritating substance to the eyes of rabbits.
Qualifier:
according to guideline
Guideline:
other: The test was performed according to "Appraisal of the safety of chemicals in foods, drugs and cosmetics, FDA (Draize) (1959)"
Principles of method if other than guideline:
Method: Draize Test
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
Amount applied: 0.1 ml
Observation period (in vivo):
up to 7 days
Number of animals or in vitro replicates:
6
Details on study design:
0.1 ml of undiluted test material was instilled into the conjunctival sac  of the left eye. The right eye, which remained untreated, served as a  control. Animals were observed for irritating effects of the cornea,  iris, conjunctivae 24, 48, 72 h and 4, 5, 6 and 7 days after treatment.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: #1,#4, #5
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: #2, #6
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.66
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Under the described conditions, 3 animals showed slight conjunctival  redness, which subsided 48 h after treatment.

 

Classification of eye irritation studies according GHS-criteria

 

Substance:Ethyl methacrylate             EMA                         CAS:97-63-2

 

Internal No.:UNTER 78-005

 

Date/Expert:06-12-15/Am

 

Animal No.

Corneal opacity/Hornhauttrübung[Scores]

 

Mean Draize score

Reversibility

[scores]

Hazard category

after 24 h

after 48 h

after 72 h

in 7 days

in 21 days

 

1

0

0

0

0

0

n.d.

 

2

0

0

0

0

0

n.d.

 

3

0

0

0

0

0

n.d.

 

4

0

0

0

0

0

n.d.

 

5

0

0

0

0

0

n.d.

 

6

0

0

0

0

0

n.d.

 

 

 

 

 

 

 

 

none

 

 

 

 

 

 

 

 

Animal No.

Iritis/Regenbogenhautentzündung[Scores]

 

Mean Draize score

Reversibility

[scores]

Hazard category

after 24 h

after 48 h

after 72 h

in 7 days

in 21 days

 

1

0

0

0

0

0

n.d.

 

2

0

0

0

0

0

n.d.

 

3

0

0

0

0

0

n.d.

 

4

0

0

0

0

0

n.d.

 

5

0

0

0

0

0

n.d.

 

6

0

0

0

0

0

n.d.

 

 

 

 

 

 

 

 

none

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Animal No.

Conjunctiva redness (erythem) /Bindehautrötung[Scores]

 

Mean Draize score

Reversibility

[scores]

Hazard category

after 24 h

after 48 h

after 72 h

in 7 days

in 21 days

 

1

0

0

0

0

0

n.d.

 

2

2

0

0

0,66

0

n.d.

 

3

1

0

0

0,33

0

n.d.

 

4

0

0

0

0

0

n.d.

 

5

0

0

0

0

0

n.d.

 

6

1

0

0

0,33

0

n.d.

 

 

 

 

 

 

 

 

none

 

 

 

 

 

 

 

 

Animal No.

Conjunctiva chemosis /Bindehautödem[Scores]

 

Mean Draize score

Reversibility

[scores]

Hazard category

after 24 h

after 48 h

after 72 h

in 7 days

in 21 days

 

1

0

0

0

0

0

n.d.

 

2

0

0

0

0

0

n.d.

 

3

0

0

0

0

0

n.d.

 

4

0

0

0

0

0

n.d.

 

5

0

0

0

0

0

n.d.

 

6

0

0

0

0

0

n.d.

 

 

 

 

 

 

 

 

none

 

 

Classification:

Hazard Category

 

none

 


 

n.d. = no data

 

Classification Criteria for serious Eye Damage/Eye Irritation

 

Category 1

 

  • Irreversible damage to cornea, iris, conjunctiva 21 days after exposure in at least one animal
  • Mean Draize score in 2 of 3 animals:

     corneal opacity≥ 3

     iritis ≥ 1,5

 

 

Category 2

 

  • Reversible adverse effects on cornea, iris, conjunctiva
  • Mean Draize score in 2 of 3 animals:

corneal opacity≥1

iritis≥1

redness≥2

chemosis≥2

 

 

Subcategory 2A

 

  • Reversible in 21 days

 

Subcategory 2B

 

  • Reversible in 7 days
Interpretation of results:
not irritating
Conclusions:
Classification: not irritating
Executive summary:

In a primary eye irritation study according to Appraisal of the Safety of Chemicals in foods, drugs and cosmetics, FAD Draize (1959) 0.1 mL undiluted ethyl methacrylate was instilled into the conjunctival sac of the left eye of 6 New Zealand White rabbits, (2.4 -2.6 kg body weight) for 72 hours (not rinsed). Animals were observed for 7 days. Irritation was scored according to Draize scoring and re-evalutated according CLP criteria. Only slight conjunctival redness (max. score 0.66) was observed in 3/6 animals which was rapidly reversible within 48 h.

In this study ethyl methacrylate is not irritating to eyes.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation 

The assessment of skin irritation is based on three studies with EMA. Only data for the shaved skin were used for evaluation. In studies carried out with more than three animals both approaches, the overall mean score and the average score determined per animal, were used for evaluation.

1. Sterner and Stiglic (1977a): Application: 2 h; occlusive (shaved and shaved/scarified); six New Zealand White rabbits were assigned to study.

In order to investigate the reproducibility of the effects, each rabbit had two separate dose sites (shaved and shaved/scarified), which were treated with 0.5 ml of undiluted EMA. In addition, two untreated areas (shaved and shaved/scarified) were used as the control. Only reactions which were different from those of the control were evaluated as positive reactions. For each treated dose site, 0.5 ml of undiluted test material was soaked onto a gauze patch (approx. 6 cm²) which was held in place with adhesive tape on the shaved and shaved/scarified skin of the test animals. The animals were fixed in a holding device and their bodies were wrapped in a rubberised cloth for 2 h. After this time, the dressing and adhesive tape were removed and the local reactions were examined. Twenty-four and 72 h after application, the examinations were repeated. The test result is the average of the scores of the 24 and 72 h examination.

Results: Shaved, intact skin: Mean erythema scores (24 + 72 h) per animal were 0 (four animals) and 1.0 (two animals) . Evaluated with the second approach the overall mean erythema score was 0.33. Mean oedema scores (24 + 72 h) per animal were 0 (five animals) and 0.5 (one animal). Overall mean oedema score (24 + 72 h) was 0.083 Some erythema and oedema scores persisted at point 72 h.

 

2. Sterner and Stiglic (1977b): Exposure time: 24 h; occlusive (shaved and shaved/scarified); six New Zealand White rabbits were assigned to study. 

The testing animals were restrained in stocks and the fur removed by clipping. Half of the exposed area was abraded and the other half remained intact. 0.5 ml of EMA was applied to shaved intact and abraded skin sites and covered with a patch. Two areas remained untreated as control. The animals were fixed and covered with a rubber cloth for 24 h. Then the patches were removed and the local reactions were evaluated after 24 and 72 h in contrast to the control. The test result is the average of the scores of the 24 and 72 h examination.

 

Results: Shaved, intact skin: Mean erythema scores (24 + 72 h) per animal were 0 (four animals), 0.5 (one animal) and 1.0 (one animal). Evaluated with the second approach the overall mean erythema score was 0.25. Mean oedema scores (24 + 72 h) per animal were 0 for all six animals. Erythema scores persisted at point 72 h.

 

3. Poole (1980): Exposure time: 24 h; occlusive; six New Zealand White rabbits.

The testing animals were restrained in stocks and the fur removed by clipping. Half of the exposed area was abraded and the other half remained intact. 0.5 ml of EMA was applied to the shaved intact and abraded skin sites and covered with surgical gauze. The area was then wrapped with impervious tape and a stockinette sleeve. Test material remained in contact for 24 h and then removed. Irritation scores were determined at 24 and 72 h after patch removal. The test result is the average of the scores of the 24 and 72h examination.

Result: Shaved, intact skin: Mean erythema scores (24 + 72 h) per animal were 0.5, 1.5 and 2 each. Mean oedema scores (24 + 72 h) were 2 (two animals) and 1.5, 2, 2.5 and 3 each for one animals. Evaluated with the second approach the overall mean erythema score was 1.34 and overall mean oedema score (24 + 72 h) was 1.67. Erythema scores persisted in 4 animals at point 72 h and oedema score in all animals.

 

Summary and discussion of skin irritation

For EMA three studies with each 72 h observation time are available. Each study was carried out with 6 animals. Both approaches, the overall mean score and the average score determined per animal, were used for evaluation. In two studies of the same publication (Sterner and Stiglic, 1977 and 1977a) all irritation scores were < 2.3 after an exposure time of 2 h in one study and 24 h (highest mean scores were 0.5). In the third study (Poole, 1980a) mean oedema scores in 2/6 animals were > 2.3. Overall erythema score in six animals was 1.34 and oedema score 1.67. In this study exposure time was 24 h and observation time 72 h, too short to demonstrate reversibility, therefore in the purpose of precautionary principle, EMA is considered as irritating to skin.

 

Comparison with criteria

In none of three studies EMA the criteria for classification as skin irritant in accordance with CLP criteria were reached. In one study mean oedema scores were > 2.3 in 2/6 animals. But as observation time was too short to demonstrate full reversibility, EMA is considered as irritating to skin.

 

Conclusion on classification and labelling
CLP classification: Skin Irrit 2, H315: Causes skin irritation.
Present Annex VI classification is confirmed.

 

Eye irritation

The assessment of eye irritation is based on two studies with EMA. All studies were with 6 animals, therefore both approaches the overall mean score and the average score determined per animal, were used for evaluation.

 

1. In a study following an FDA guideline (Draize protocol) EMA (0.1 ml) was instilled into the right eye of six New Zealand White rabbits (Poole, 1980a). The lids were then gently held together for one second. The test eyes were not washed out following the instillation. The left eye remained untreated for control. The eyes were examined at 24, 48 and 72 h from beginning of test. Eye irritation was scored for signs of corneal damage (density, area), iris reaction and lesions of the conjunctivae (erythema, chemosis and discharge). Additionally, the cornea was examined with the aid of fluorescein after recording the observations at 24 h. Highest mean cornea score (24+48+72 h) was 0.33 in 2/6 animals, no animal showed iritis, 3/6 animals showed conjunctival erythema > 2 and 2/6 animals cunjunctival chemosis > 2. Scores showed clear tendency in rapid reversibility but during the short observation time (72 h) full reversibility could not be demonstrated in all animals (scores in 2/6 animals were fully reversible).

In this study EMA is considered as slightly irritating to eyes (mean erythema scores over a period of 24, 48 and 72 h: 0.33 - 2.66, mean chemosis scores: 0 - 2.66).

2.In a primary eye irritation study according to Appraisal of the Safety of Chemicals in foods, drugs and cosmetics, FAD Draize (1959) 0.1 mL undiluted ethyl methacrylate was instilled into the conjunctival sac of the left eye of 6 New Zealand White rabbits, (2.4 -2.6 kg body weight) for 72 hours (not rinsed) (Sterner W, Stiglic AW 1978) . Animals were observed for 7 days. Irritation was scored according to Draize scoring and re-evalutated according CLP criteria. Only slight conjunctival redness (max. score 0.66) was observed in 3/6 animals which was rapidly reversible within 48 h.

In this study ethyl methacrylate is not irritating to eyes.

 

Summary and discussion of eye irritation

For EMA two studies with 6 animals are available. Evaluation was carried out with both approaches, the overall mean score and the average score determined per animal. In one study (Sterner W, Stiglic AW 1978) only slight erythema was observed which was fully reversible within 48 h. In another study (Poole 1980)mean erythema scores over a period of 24, 48 and 72 h were 0.33 - 2.66 and mean chemosis scores: 0 - 2.66. Scores shoed clear tendency to rapid reversibility but within the short observation time of 72 h full reversibility could not be demonstrated in all animals.

Comparison with criteria

EMA did not reach the criteria for classification as eye iritant in accordance with CLP criteria. In one study mean erythema scores were > 2 in 3/6 animals and rapid but not full reversibility within 72 h was demonstrated. EMA is considered as not irritating to eyes.

Conclusion on classification and labelling
CLP classification: Eye Irrit 2, H319: Causes eye irritation.
Present Annex VI classification is not confirmed.

Respiratory irritation

In a no guideline-related inhalation study (Jones, 2002) in five male F344 rats using specialist histopathology techniques to study the nasal tissues, several alkyl methacrylates were tested by single whole body exposure of 200 ppm (one dose group) for 6 h. Methyl methacrylate (MMA) and ethyl methacrylate under comparable exposure conditions resulted in histopathological findings consistent with nasal irritation. The effect of EMA was slighty less than with MMA.In the case of MMA the mode of action by which olfactory lesions are formed has been shown to be due to hydrolysis of the parent ester to MAA, an irritant and corrosive substance, by carboxylesterases in the olfactory epithelium (EU Chemicals Bureau 2002). As this MOA has been shown to occur with many other common esters, ethers and acetates it is anticipated to occur with EMA.

Conclusion on classification and labelling

CLP classification: STOT Single Exp.3, H335: May cause respiratory irritation

Present classification is not confirmend


Effects on skin irritation/corrosion: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin irritation

In none of three studies EMA the criteria for classification as skin irritant in accordance with CLP criteria were reached. In one study mean oedema scores were > 2.3 in 2/6 animals. But as observation time was too short to demonstrate full reversibility, EMA is considered as irritating to skin (Cat 2) according to CLP and UN-GHS criteria.

Eye irritation

It is considered that ethyl methacrylate possess the potential for slight irritation effects on the rabbit eye, which were below the criteria for classification according to 67/548/EEC and CLP criteria, respectively. No classification based on data, thus no classification according to UN-GHS, while in EU the Annex VI classification has to be accepted for the time being.

Irritation of the respiratory tract

Based on results of studies in animals and by analogy to human data with MMA, ethyl methacrylate is classified as irritant to the respiratory tract (STOT single exposure Cat. 3 according to CLP and UN GHS criteria, respectively).