2-hydroxyethyl methacrylate

Endpoint summary

Description of key information

Skin irritation: not irritating to rabbits in a study according to Appraisal of the safety of chemicals in food, drugs and cosmetics by the Staff of the Division of Parmacology, FDA, 1959 in food, drugs and cosmetics.

 

Eye irritation: irritating to the eyes of rabbits Category 2, H319 acc. CLP Regulation 1272/2008 (Category 2B acc. UN-GHS criteria)

 

Respiratory irritation: not expected to cause respiratory irritation, e.g. due to low vapour pressure.

 

HEMA is classified acc. Annex VI of Regulation EU 1272/2008 into Skin irrit 2, H315 and Eye irrit 2, H319

 

The key study for skin irrition does not confirm the classification as skin irritant acc. EU regulation. Eye irritation is confirmed by the study of Sterner (1978). :

 

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

other: Appraisal of the safety of chemicals in foods, drugs and cosmetics (1959)

Principles of method if other than guideline:

Method: Appraisal of the safety of chemicals in foods, drugs and cosmetics by the Staff of the Division of Pharmacology, FDA, Hautgiftigkeit nach Draize (1959)

GLP compliance:

no

Specific details on test material used for the study:

Supplier: Röhm GmbH, Darmstadt, Germany
Purity: not specified in the report.
Company data in the years of the report: 0,071 bis 0,91 % methacrylic acid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.5 kg (average)
- Housing: individual cages
- Diet: rabbit standard diet (Höing 222)
- Water ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 -1 (max. limitation)
- Humidity (%): 50-60
- Photoperiod ( hrs light): 12

Type of coverage:

occlusive

Preparation of test site:

other: shaved, shaved and scarified

Vehicle:

unchanged (no vehicle)

Controls:

other: as a contol 2 areas of the treated animals were also shaved ans scrarified but remained untreated

Amount / concentration applied:

TEST MATERIAL
- Amount applied (volume): 0.5 ml

Duration of treatment / exposure:

24 hour(s)

Observation period:

72 h

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- Type of wrap if used: rubberized cloth

CONTROL.
- as a contol 2 areas of the treated animals were also shaved and scrarified but remained untreated

REMOVAL OF TEST SUBSTANCE
- Washing : no wahing was done


SCORING SYSTEM:
1. Erythema and scars formation
no erythema 0
very slight erythema 1
clear erythema 2
moderate to severe erythema 3
severe erythema (scarlet red) 4
and slightly scars formation

2. Edema formation
no edema 1
very slight edema 2
moderate edema (thickness ca. 1mm) 3
severe edema (thickness more than 4
1mm, large than the edge of the
contact)

Irritation parameter:

erythema score

Basis:

animal #1

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. DSD (overall mean).

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24 h

Score:

1

Max. score:

4

Remarks on result:

other: before end of test, animal died, not treatment related

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: mean 24+72 h

Score:

0

Max. score:

4

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 #4

Time point:

other: 24+72 h

Score:

0

Max. score:

4

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 #5

Time point:

other: 24+72 h

Score:

0

Max. score:

4

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 #6

Time point:

other: 24+72 h

Score:

0

Max. score:

4

Remarks on result:

other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: 24+72 h

Score:

0

Max. score:

4

Remarks on result:

other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: 24+72 h

Score:

0

Max. score:

4

Remarks on result:

other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: 24+72 h

Score:

0

Max. score:

4

Remarks on result:

other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).

Irritation parameter:

edema score

Basis:

animal #4

Time point:

other: 24+72 h

Score:

0

Max. score:

4

Remarks on result:

other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).

Irritation parameter:

edema score

Basis:

animal #5

Time point:

other: 24+72 h

Score:

0

Max. score:

4

Remarks on result:

other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).

Irritation parameter:

edema score

Basis:

animal #6

Time point:

other: 24+72 h

Score:

0

Max. score:

4

Remarks on result:

other: occlusive, exposure time 24 h, observation time 72 h, intact skin, reevaluated acc. DSD (overall mean).

Irritant / corrosive response data:

2/6 animals showed mean response scores for erythema of 0.5 and 1, respectively after 24 and 72 hrs or 24 hrs, respectively. Mean erythema scores in 4/6 animals were 0.
No edema scores were detected in 6/6 animals.

Original data of the test report:

Animal Nr.			Scores (24 h)	Scores (72 h)
1	shaved	Erythema and scras formation	1	0
		Edema formation	0	0
	shaved/scarified	Erythema and scras formation	2	1
		Edema formation	1	0
2	shaved	Erythema and scras formation	1	*
		Edema formation	0	*
	shaved/scarified	Erythema and scras formation	0	*
		Edema formation	0	*
3	shaved	Erythema and scras formation	0	0
		Edema formation	0	0
	shaved/scarified	Erythema and scras formation	1	0
		Edema formation	1	0
4	shaved	Erythema and scras formation	0	0
		Edema formation	0	0
	shaved/scarified	Erythema and scras formation	0	1
		Edema formation	0	0
5	shaved	Erythema and scras formation	0	0
		Edema formation	0	0
	shaved/scarified	Erythema and scras formation	0	0
		Edema formation	0	0
6	shaved	Erythema and scras formation	0	0
		Edema formation	0	0
	shaved/scarified	Erythema and scras formation	0	0
		Edema formation	0	0

*= animal died prio to the end of the test, death not attributed to the treatment with the substance

 

 

1. Primary irritation index of the shaved skin

 

Animal No.	Primary irritation index
1	0.25
2	0.25*
3	0.00
4	0.00
5	0.00
6	0.08
X1	0.08

 

 

2. Primary irritation index of the shaved/scarified skin

 

Animal No.	Primary irritation index
1	1.00
2	0.00*
3	0.50
4	0.25
5	0.00
6	0.00
X2	0.29

 

Total index: X₁ +   X₂= 0.37

 * = fragmentary value

 

Reevaluation according to OECD 404

 

	Erythema		Edema
	24h	72h	24h	72h
Animal 1	1	0	0	0
Animal 2	1	*	0	*
Animal 3	0	0	0	0
Animal 4	0	0	0	0
Animal 5	0	0	0	0
Animal 6	0	0	0	0
Mean	0,33333333	0	0	0
Total mean	0,16666667		0
	Erythema		Edema

Interpretation of results:

GHS criteria not met

Conclusions:

Classification: not irritating

Executive summary:

2 -Hydroxyethyl methacrylate was tested in a primary skin irritation test to rabbits according to "Appraisal of the safety of chemicals in food, drugs and cosmetics by the Staff of the Division of Parmacology, FDA, 1959 in food, drugs and cosmetics". 6 animals were treated with the undiluted test substance for 24 h, occlusive. After 24 hours, 2 animals showed slight erythema at the shaved intact skin (one of them died during the test not treatment related). Within 72 hours erythema were fully reversible. None of the 6 animals showed edema during the test.

Therefore in this study hydroxyethyl methacrylate is not irritating to skin according to EU regulation 1271/08 and UN-GHS requirements.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

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:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: Appraisal of the safety of Chemicals in foods, drugs and cosmetics by staff of the Division of Pharmacology, FDA acc. to Draize

Principles of method if other than guideline:

Appraisal of the safety of Chemicals in foods, drugs and cosmetics by staff of the Division of Pharmacology, FDA acc. to Draize (1959)

GLP compliance:

no

Specific details on test material used for the study:

Supplier: Röhm GmbH, Darmstadt, Germany
Purity: not specified in the report.
Company data in the years iof the report: 0,071 bis 0,91 % methacrylic acid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.4 to 2.6 kg
- Housing: individual cages
- Diet : standard diet (Höing 222)
- Water ad libitum:


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 °C
- Humidity (%): 50-60
- Photoperiod hrs light): 12

Vehicle:

unchanged (no vehicle)

Controls:

other: the right ear of the test animals remained untreated as control

Amount / concentration applied:

TEST MATERIAL
- Amount applied (volume): 0.1 ml
- Concentration: undiluted

Observation period (in vivo):

24, 48, 72 h, 4, 5, 7 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: no washing:


SCORING SYSTEM:
Scoring system for the evaluation of ear lesions Scores

1. Cornea
A. Opacity - Grade of opacity (the most opac area will be used for evaluation)

No opacity 0
Motteled or diffuse opacity
(details if iris good visible) 1
Slightly differentiated opac areas,
details of iris slightly ambiguous 2
Opac areas, no details of iris are visible,
size of pupil hardly visible 3
Opacity, iris unvisible 4

B. Size of involved total area
¼ or less but not zero 1
More than ¼, but less than ½ 2
Larger than ½ but less than ¾ 3
Larger than ¾ up to total area 4
A x B x 5 total maximum number = 80

2. Iris
A. Evaluation
Normal 0
Increasing wrinkle formation (washy trabecules )
Blood overfilling, swelling, vascular dilatation at
the edge of cornea (when one or more symptoms
occur) iris shows still light reaction (delayed
reaction is deemed to be positive) 1
No reaction against light, bleeding, changes in
iris structure (one or more symptoms) 2

A x 5 total maximum number =10

3. Conjunctiva
A. Redness
Vascular normal 0
Vascular definitely more than normal injected 1
More diffuse crimson colour, single vascular
difficult to identify 2
Diffuse flesh colour 3

B. Chemosis
No swelling 0
More than normal swelling (including nictitating membrane) 1
Definite swelling with lifting the lids 2
Swelling with semi-closed lids 3
Swelling that lids are more than semi-closed or totally
closed 4

C. Secretion
No secretion 0
Every increased secretion (not included the physiological
secretion at the inner canthus) 1
Secretion with moistening the lids and the
neighboring hairs 2
Secretion with wettening the lids and the neighboring
hairs largely beyond the eye 3

Total number (A+B+C) x 2 total maximum number = 20
The total number for the eye is the summation of the scores for cornea, iris and conjunctiva

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal: # 2, '3, #4, #6

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal: #1, #5

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal: #2, #3, #4, #6

Time point:

24/48/72 h

Score:

0.66

Max. score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal: #2, #3

Time point:

24/48/72 h

Score:

1.66

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal: #1, #5

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal: #2, #3, #4, #6

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.66

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritant / corrosive response data:

HEMA produced in 6/6 animals a positive response of corneal opacity >= 1 calculated as the means scores following grading at 24, 48 and 72 hours which were fully reversible within 7 days in all animals. Mean scores of iritis, conjunctival redness and conjunctival edema were below the CLP classification criteria and were also fully reversible within 7 days in all animals.

Interpretation of results:

Category 2B (mildly irritating to eyes) based on GHS criteria

Conclusions:

Classification acc. CLP citeria: : irritating to eyes, Category 2, H319
Classification acc. GHS citeria: : mildly irritating to eyes, Category 2B

Executive summary:

2 -Hydroxyethyl methacrylate was tested in an eye irritation test to rabbits according to the Appraisal of the safety of Chemicals in foods, drugs and cosmetics by staff of the Division of Pharmacology, FDA acc. to Draize (1959). 6 New Zealand White rabbits received 0.1 ml of the undiluted substance into the right eye. The eyes remaind unwashed. The eye reactions were observed after 24, 48, 72 hrs and 4, 5 and 7 days. The study was reevaluated according to UN-GHS criteria. 6/6 animals had opacity scores >= 1 which were reversible within 7 days. Based on this HEMA is classified acc. CLP regulation into Category 2 (H319) and acc. UN-GHS into Category 2B.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

HEMA has been evaluated in skin irritation studies in experimental animals.

The skin irritation potential of HEMA has been evaluated in a test in rabbits according to "Appraisal of the safety of chemicals in food, drugs and cosmetics by the Staff of the Division of Parmacology, FDA, 1959 in food, drugs and cosmetics" (Sterner, Stiglic, 1977).  This study was assigned a Klimisch rating of 2, reliable with restriction. Undiluted HEMA was applied with occlusion to the scarified and non-scarified skin of six rabbits for 24 hr. 2/6 animals had erythema scores of 1 after 24 hrs (one animal died not treatment related within 24 hrs.). After 72 hours none of the remaining five animals showed erythema. 0/6 animals showed edema after 24 and 72 hrs. HEMA was found to be not irritating to the rabbit skin acc. CLP and GHS classification criteria. Other available studies were reviewed and judged to be not reliable or not assignable. 

 

HEMA has been evaluated in eye irritation studies in experimental animals.

The key study (Sterner, 1977) was assigned a Klimisch rating of 2, reliable with restriction. The test was performend in rabbits  according to the Appraisal of the safety of Chemicals in foods, drugs and cosmetics by staff of the Division of Pharmacology, FDA acc. to Draize (1959). The study was reevaluated according to UN-GHS criteria.  6/6 animals had opacity scores >= 1 which were reversible within 7 days. HEMA is classified acc. CLP regulation into Category 2 (H319) and acc. UN-GHS into Category 2B.

 

 

In absence of directly applicable studies, HEMA has been evaluated for its respiratory irritation potential in a weight-of-evidence assessment.

In conclusion, there is no relevant evidence that HEMA can cause specific effects on the human respiratory tract after a single exposure based on following considerations (full assessment attached):

• HEMA has a relatively low vapour pressure;


• HEMA is only a weakly potent irritant, reaching just criteria of eye irritation Cat 2B under UN-GHS, but no classifiable effects on skin irritation;


• No local effects have been observed in a subacute inhalation study in rats exposed to maximum technically achievable concentrations of HEMA;


• The concentration of the low volatile, corrosive impurity MAA is at least five times below the respective SCL that triggers classification as respiratory irritant; and


• MAA, as primary metabolite, can theoretically cause irritative effects in the respiratory tract of rats in atmospheres saturated with HEMA. However, it is implausible that relevant local concentrations in humans can be reached, even in combination with the few MAA molecules coming from the impurity.

Justification for classification or non-classification

HEMA is classified acc. Annex VI, EU regulation 1272/2008 into Category Skin irrit 2, H315 and Eye irrit 2, H319. 

Experimental studies do not confirm the classification of HEMA as skin irritant: Therefore under UN-GHS criteria HEMA is not classified for skin irritation, for eye irritation HEMA ist classified with Category 2B, H320.

Based on considerations within a comprehensive weight-of-evidence assessment, there is no basis for classification of HEMA as respiratory irritant under EU CLP or UN-GHS.