Registration Dossier

Administrative data

Description of key information

In a well documented study methacrylic anhydride was found to cause irritating effects to skin, category 2. The oberservation period was however only 72 hours. In an eye irritation study the substance caused severe eye damage without reversibility within 7 days.

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:
27.03.1984 - 30.03.1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well documented study but exposure time 24 h instead of 4h hours and observation time only 72 hours instead of 14 days.
Qualifier:
according to
Guideline:
other: Journal officiel de la Republique Francaise, 21 February 1982
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source Nottingham University, School of Agriculture, Sutton Bonington, Leics & Rosemead Rabbits Ltd., Lea Valles, Essex
- Age at study initiation: 12-16 weks
- Weight at study initiation: 2.78-3.10 kg
- Housing: All animals were individually housed in suspended metal cages
- Diet (e.g. ad libitum): standard laboratory (rabbit diet, A.W. Tindall Limited, Holbeach, Lincolnshire)
- Water (e.g. ad libitum): tap water


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 +/- 2.5 °C
- Humidity (%): 52-58 %
- Air changes (per hr): 10 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle
Type of coverage:
occlusive
Preparation of test site:
other: intact and abraded
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
24 hours
Observation period:
1 hour following removal of the patches and 48 hours later (72 hours after application of test material)
Number of animals:
6
Details on study design:
Approximately twenty-four hours prior to the commencement of the test each of a group of six rabbits were prepared by closely clipping the hair from the dorsal/flank areas using Oster A5 professional animal clippers (size 40 cutters). Immediately before treatment on the day of the test the right side of each rabbit was abraded using the tip of a scalpel blade. Abrasion consisted of superficial skin injury sufficient to disturb the stratum corneum but not deep enough to cause bleeding. The left side of each rabbit remained intact.
A 0.5 ml aliquot of the test material was introduced under a composite patch which consisted of a 2.5 cm x 2.5 cm square of absorbant lint BPC backed by a 4.0 cm x 4.0 cm square of absorbant lint BPC with a final backing of a 3.0 cm x 3.0 cm square of polythene. The patches were applied to the abraded and intact test sites of each animal and held securely in position by two lengths of Sleek adhesive strapping (Smith & Nephew Limited) in the form of a cross. An elasticated corset was then applied (Seton's Tubigrip) to prevent interference with the patches. The rabbits were then returned to their cages where they could move about, eat and drink normally.
Twenty-four hours later the corset was removed from each animal and the patches were carefully taken off the test sites. Any residual test material was removed by gentle swabbing with cotton wool soaked in lukewarm water or other suitable solvent. Approximately one hour following removal of the patches and 48 hours later (i.e 72 hours after the test material was applied) the intact and abraded sites of each animal were observed for evidence of irritation. Reactions were scored according to i.e Draize J.H (1959) Association of Food & Drug Officials of the USA, Austin, Texas, "The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics".
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24+72 h
Score:
2.17
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24+72 h
Score:
2.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #1
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #2
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #3
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #4
Time point:
72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #5
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin
Irritation parameter:
edema score
Basis:
animal #6
Time point:
72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: shaved skin

Skin reaction

Skin site

Readings

(hours)

Individual scores

Total

 Rabbit number

1

2

3

4

5

6

 

Erythema and Eschar formation

Intact

24

2

3

2

2

2

2

13

 

72

1

2

3

3

2

2

13

Abraded

24

2

3

2

2

2

2

13

 

72

2

2

3

3

2

3

15

Oedema Formation

Intact

24

4

4

4

4

4

2

22

 

72

2

1

1

2

1

1

8

Abraded

24

4

4

4

4

4

2

22

 

72

2

2

1

2

1

1

9

 

Group total score

115

Primary irritation index: Group total score/24 = 4.8

 

Reevaluation according GHS criteria

Only animals with shaved skin were evaluated

 

 

Erythema

Edema

Animal No.

24 h

72h

24h

72h

1

2

1

4

2

2

3

2

4

1

3

2

3

4

1

4

2

3

4

2

5

2

2

4

1

6

2

2

2

1

Mean value

2.166

2.5

 

 

Classification according GHS: Category 2 (Erythema < 2,3; Edema > 2,3)

 

Remark:

Exposure time: 24 hours instead of 4 hours

Study was too short for a clear statement of reversibility because there was no observation after 72 hours.

 

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
In this study methacrylic anhydride was irritating to skin, GHS/OECD criteria Catregory 2. However the exposure time was 24 h instead of 4 h and the observation period only 72 h instead of 14d.
Executive summary:

In a skin irritation study (1984) acc. Journal officiel skin irritation test with 6 New Zealand White rabbits and an exposure time of 24 h (occlusive) methacrylic anhydride was irritating to skin. Observation time was too short for a clear statement of reversability. (Only 72 h instead of 14 h). Therefore methacrylic anhydride has to be classified acc. OECD GHS criteria as follows: Skin irritating Category 2

NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

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:
09.04.1984 - 03.05.1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented guideline study. Observation period only 7 days instead of 21 days.
Qualifier:
according to
Guideline:
other: Journal Officiel de la Republique Francaise 21 April 1971 and 5 June 1973
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Supplied by Nottingham University.& School of Agriculture, Sutton Bonington, Leics.
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.60-3.10 kg
- Housing: individually in suspended metal cages
- Diet (e.g. ad libitum): free access to a standard laboratory diet (Rabbit Diet, A.W. Tindall Limited, Holbeach, Lincolnshire) ad libitum.
- Water (e.g. ad libitum): free access to tap water
- Acclimation period: minimum period of five days prior to the start of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-4.5
- Humidity (%): 50-60 %
- Air changes (per hr): 10 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hour light/darl cycle

Vehicle:
unchanged (no vehicle)
Controls:
other: The contralateral eye remained untreated and was used for control purposes.
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
On the day of the test a 0.1 ml aliquot of the test material was instilled into one eye of each rabbit by gently pulling the lower lid away from the eyeball to form a cup into which the test material was dropped. The eyelids were then held together for approximately one second and the animal released. The contralateral eye remained untreated and was used for control purposes.
Observation period (in vivo):
Assessment of damage/irritation was made 1, 2, 3, 4 and 7 days following treatment
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): not done


SCORING SYSTEM: (Draize J.H. 1959, Assoc. of Food and Drug Officials of the USA, Austin, Texas, "The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics").

TOOL USED TO ASSESS SCORE: hand-slit lamp / biomicroscope / fluorescein: Examination of the eye was facilitated by the use of a
standard ophthalmoscope (Keeler) ~ Observation of corneal opacity may be carried out under ultra-violet illumination (Mineralight
UVSL-58) preceded by the instillation into the eye of 0.05 ml of fluorescein B.P.
Irritation parameter:
cornea opacity score
Basis:
animal: #1, 2 and 3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: observation time only 7 days
Irritation parameter:
cornea opacity score
Basis:
animal: # 4 and 6
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: observation time only 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: observation time only 7 days
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: observation time only 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: observation time only 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: observation time only 7 days

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)

1

2

3

2

Glanzlos

n.d.

 

2)

2

2

2

2

2

n.d.

 

3)

2

2

2

2

2

n.d.

 

4)

1

2

2

1,67

1

n.d.

 

5)

1

1

1

1

3

n.d.

 

6)

1

2

2

1,67

Glanzlos

n.d.

 

 

1,33

1,83

2

1,72

 

 

 

 

 

 

 

 

 

 

 

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)

1

1

1

1

0

n.d.

 

2)

1

1

1

1

0

n.d.

 

3)

1

1

1

1

0

n.d.

 

4)

1

1

1

1

0

n.d.

 

5)

1

1

1

1

1

n.d.

 

6)

1

1

1

1

0

n.d.

 

 

1

1

1

1

0,17

 

 

 

 

 

 

 

 

 

 

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)

3

3

3

3

2

n.d.

 

2)

3

3

3

3

2

n.d.

 

3)

3

3

3

3

2

n.d.

 

4)

3

3

3

3

2

n.d.

 

5)

3

3

3

3

3

n.d.

 

6)

3

3

3

3

2

n.d.

 

 

3

3

3

3

2,17

 

 


 

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)

4

4

4

4

2

n.d.

 

2)

4

4

4

4

3

n.d.

 

3)

4

4

4

4

3

n.d.

 

4)

4

4

4

4

2

n.d.

 

5)

4

4

4

4

3

n.d.

 

6)

4

4

4

4

3

n.d.

 

 

4

4

4

4

2,67

 

 

 

 

Classification:

Hazard Category

 

1

because there is no reversibility after 7 d

 




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 opacity1

iritis1

redness2

chemosis2

 

 

Subcategory 2A

 

  • Reversible in 21 days

 

Subcategory 2B

 

  • Reversible in 7 days
Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Executive summary:

Methacrylic anhydride was tested in an eye irritation test. The mean scores for corneal opacity , iritis and conjunctiva were not reversible within 7 days. Therefore methacrylic anhydride is classified into Category 1 (irreversible effects on the eyes).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Methacrylic anhydride was tested in two skin irritation studies, both with 24 hrs occlusive treatment. In one study there were found slight irritating effects in two animals while in another study, the key study, it was found to be irritating in six animals, category 2. With an observation time of 72 hours, both studies were too short for clear statement of reversibility. Methacrylic anhydride is less irritating than its hydrolysis product methacrylic acid. As methacrylic acid is smaller than methacrylic anhydride it will permeate faster into skin. Therefore a higher ammount of methacrylic acid will be available compared to methacrylic acid, hydrolysed from methacrylic anhydride after permeation into the skin.

Methacrylic anhydride caused severe eye damage in an eye irritation test according guideline. Within 7 days, no reversibilty was observed. Methacrylic anhydride is corrosive to eyes, category 1.

Based on the irritation properties of the substance, its vapour pressure and findings in repeated dose inhalation studies with the primary metabolite MAA, MAAH should be classified for irritation properties to the respiratory tract.


Justification for selection of skin irritation / corrosion endpoint:
Most sensitive study was chosen

Justification for selection of eye irritation endpoint:
Only one study available

Justification for classification or non-classification

Methacrylic anhydride fulfils the criteria for skin irritation category 2, for eye irritation/corrosion category 1 and for STOT single/ irritation to the respiratory tract category 3 (1272/2008/EC and UN GHS).