Methacrylic acid, monoester with propane-1,2-diol

Endpoint summary

Description of key information

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

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

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

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:

test procedure in accordance with national standard methods 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:

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: 0,005 to 1 % 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, #2, #3, #4, #5, #6

Time point:

other: 24/72h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal: #1, #2, #3, #4, #5, #6

Time point:

other: 24/72h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

0/6 animals had erythema or edema after 72 hours. Mean scores for erythema and edema after 24 and 72 hrs were 0.

 

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

 

1. Primary irritation index of the shaved skin

 

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

 

 

2. Primary irritation index of the shaved/scarifized skin

 

Animal No.	Primary irritation index
1	0.00
2	1.00
3	0.50
4	0.00
5	0.00
6	0.50
X2	0.33

 

Total index: X₁ +   X₂= 0.33

 

 

• = fragmentary value

 

 

Reevaluation according to OECD 404

 

	Erythema		Edema
	24h	72h	24h	72h
Animal  1	0	0	0	0
Animal  2	0	0	0	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	0	0	0
Total mean	0		0
	Erythema		Edema

 

 

Interpretation of results:

GHS criteria not met

Conclusions:

Classification: not irritating

Executive summary:

2-Hydroxypropyl 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 New Zealand White rabbits were exposed to undiluted HPMA on the shaved and shaved + scarified skin under occlusive conditions for 24 hours. The  observation time was  72 hrs. No erythema or edema were observed in any animal after 24 and 72 hrs at the shaved skin.

Therefore in this study 2-hydroxypropyl 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

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1981-08-24 to 1981-09-14

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific principles, accepted for assessment.

Guideline:

other:

Version / remarks:

"Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics'' (1959), the US Association
of Food and Drug Officials (APDO).

Principles of method if other than guideline:

0.1 ml test substance was placed on the corneal surface instead of introducing
it into the conjunctival sac inside the lower lid;

GLP compliance:

no

Specific details on test material used for the study:

Purity: 99.2 %
Impurities: low boilers: 0.03 %
methacrylic acid: 0.2 %
high boilers: 99 %
propylene oxide: 5 ppm
propyleneglycol-
dimethacrylate : none detected
Inhibitor : hydroquinone monomethyl ether: 5 ppm

Species:

rabbit

Strain:

New Zealand White

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

Amount applied: 0.1 ml

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

9

Details on study design:

Comment: The application of HPMA in this study was onto the cornea (current guidelines specify test material application into conjunctival sac. This methodology was popular
in the early 1980' rabbits numbered 1 - 6 inclusive (unwashed eyes); rabbits numbered 7 - 9 were washed (flooded with water) approximately 20 - 30 seconds after dosing.( Data of rabbits with unwashed were not for reevaluation).

Irritant / corrosive response data:

Scoring system described under "Any other information on materials and methods incl. tables" Results of the test are under Any other information on results incl. tables"

Mean scores of cornea after 24/48/72 hrs were in the range of 11-25 for 6/6 animals and therefore a slight response. 21 days after exposure 1/6 animals showed slight sings of corneal opacity (scores 10/80). Mean scores of iris and conjunctivae were less pronounced and were fully reversible within 7 days (iris) or 21 days (conjunctivae), respectively.

 

Time point	Structure	Rabbit Number, Value
		1	2	3	4	5	6
24 h	CORNEA IRIS CONJUNCTIVAE	20.0 5.0 12.0	10.0 2.5 12.0	15.0 0.0 12.0	10.0 5.0 12.0	15.0 2.5 12.0	15.0 5.0 12.0
48 h	CORNEA IRIS CONJUNCTIVAE	20.0 0.0 4.0	15.0 0.0 4.0	20.0 0.0 4.0	15.0 0.0 4.0	20.0 2.5 4.0	15.0 2.5 12.0
72 h	CORNEA IRIS CONJUNCTIVAE	15.0 2.5 2.0	15.0 0.0 10.0	15.0 2.5 6.0	20.0 0.0 2.0	15.0 0.0 8.0	15.0 0.0 6.0
7 days	CORNEA IRIS CONJUNCTIVAE	5.0 0.0 0.0	0.0b 0.0 0.0	0.0 0.0 0.0	0.0 0.0 0.0	40.0b 0.0 2.0	0.0b 0.0 0.0
21 days	CORNEA IRIS CONJUNCTIVAE	0.0 0.0 0.0	0.0 0.0 0.0	0.0 0.0 0.0	0.0 0.0 0.0	10.0b 0.0 0.0	0.0 0.0 0.0

B = blood vessels from cornea

 

In animal 5 corneal effects increased on day 7 from 15 (day 4) to 40 (day 7) and persited by 10 on day 21 (blood vessels cornea). In 5/6 animals all effects decreased after 4 days. It cannot be excluded that observations of animal 5 are caused by lesions at substance application, since the test substance has been applicated directly to the cornea instead of the conjunctival sac or lesion has been provoked during observation. Effects in 5/6 animals  were fully reversible within 7 days. In one animal very slight corneal effects (10 of max. 80 scores) persited on day 21.

(Due to the summarized report where scores have been reported after multiplying with a factor, and single scores are not avaiable, reevaluation according the GHS method is not possible.)

Interpretation of results:

other: slightly irritating

Conclusions:

HPMA is slightly irritating

Executive summary:

2-Hydroxypropyl methacrylate was tested in an eye irritation test acc. "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics'' (1959), the US Association of Food and Drug Officials (APDO). 01. ml undiluted test material was applicated directly onto the cornea. The eyes were not  washed. Effects in 5/6 animals were fully reversible within 7 days. In one animal very slight corneal effects (10 of max. 80 scores) persited on day 21. This effect is expected to be caused by direct application or lesion at observation.

Reference 2

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:

other: 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 by staff of the Division of Pharmacology, FDA acc. to Draize

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: 0,005 bis 1 % 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:

yes, concurrent no treatment

Amount / concentration applied:

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

Duration of treatment / exposure:

till end of observation period

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, #2, #3, #4, #6

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 4 days

Remarks on result:

positive indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal: #1, #2, #3, #4, #5, #6

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal: #3, #4, #6

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 4 days

Remarks on result:

probability of mild irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

fully reversible within: 4 days

Remarks on result:

probability of moderate irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 4 days

Remarks on result:

probability of moderate irritation

Irritation parameter:

chemosis score

Basis:

animal: #1, #2, #3, #5

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal: #4, #6

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

HPMA produced corneal opacity scored 1 in 5/6 animals which was fully reversible within 4 days in all animals. This result triggers classification for eye irritation into Category 2.
One animal showed conjunctival redness scored 2. Iritis and chemosis were < 1 or < 2, respectively in all other animals

		Day
Animal No. 1		1	2	3	4	5	6	7
1. Cornea	A	1	1	1	0	0	0	0
	B	2	2	2	0	0	0	0
2. Iris	A	0	0	0	0	0	0	0
3. Conjunctiva	A	2	1	1	0	0	0	0
	B	0	0	0	0	0	0	0
	C	1	1	1	0	0	0	0

 

		Day
Animal No. 2		1	2	3	4	5	6	7
1. Cornea	A	1	1	1	0	0	0	0
	B	2	2	2	0	0	0	0
2. Iris	A	0	0	0	0	0	0	0
3. Conjunctiva	A	2	2	2	0	0	0	0
	B	0	0	0	0	0	0	0
	C	1	1	1	0	0	0	0

 

		Day
Animal No. 3		1	2	3	4	5	6	7
1. Cornea	A	1	1	1	0	0	0	0
	B	2	2	2	0	0	0	0
2. Iris	A	0	0	0	0	0	0	0
3. Conjunctiva	A	2	1	0	0	0	0	0
	B	0	0	0	0	0	0	0
	C	1	1	0	0	0	0	0

 

		Day
Animal No. 4		1	2	3	4	5	6	7
1. Cornea	A	1	1	1	0	0	0	0
	B	2	2	2	0	0	0	0
2. Iris	A	0	0	0	0	0	0	0
3. Conjunctiva	A	2	1	0	0	0	0	0
	B	1	0	0	0	0	0	0
	C	1	1	0	0	0	0	0

 

		Day
Animal No. 5		1	2	3	4	5	6	7
1. Cornea	A	0	0	0	0	0	0	0
	B	0	0	0	0	0	0	0
2. Iris	A	0	0	0	0	0	0	0
3. Conjunctiva	A	1	0	0	0	0	0	0
	B	0	0	0	0	0	0	0
	C	2	0	0	0	0	0	0

 

		Day
Animal No. 6		1	2	3	4	5	6	7
1. Cornea	A	1	1	1	0	0	0	0
	B	2	2	2	0	0	0	0
2. Iris	A	0	0	0	0	0	0	0
3. Conjunctiva	A	2	1	0	0	0	0	0
	B	1	0	0	0	0	0	0
	C	3	1	0	0	0	0	0

 

 

 

Summary of the eye observations
	Day
Animal No.	1	2	3	4	5	6	7
1	16	14	14	0	0	0	0
2	16	16	16	0	0	0	0
3	16	14	10	0	0	0	0
4	18	14	10	0	0	0	0
5	6	0	0	0	0	0	0
6	22	14	10	0	0	0	0
Mean	15.67	12	10	0	0	0	0

 

Interpretation of results:

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

Conclusions:

HPMA is irritating to eyes. Classification: Category 2, H319 (CLP criteria) and Category 2B (GHS criteria)

Executive summary:

2 -Hydroxypropyl 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 were treated with 0.1 ml of the undilited test substance and were observed for 7 days. HPMA produced corneal opacity scored 1 in 5/6 animals which was fully reversible within 4 days in all animals. 
One animal showed conjunctival redness scored 2. Iritis and chemosis were < 1 or < 2, respectively in all other animals
The study was reevaluated according to GHS criteria and EU regulation 1272/2008.  The substance is irritating to eyes, Category 2B (GHS criteria) and Category 2, H319 (EU regulation 1272/2008, CLP criteria).

 

 

 

     

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation

In the key study (Sterner, 1977) HPMA 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 Pharmacology, FDA, 1959 in food, drugs and cosmetics". 6 New Zealand White rabbits were exposed to undiluted HPMA on the shaved and shaved + scarified skin under occlusive conditions for 24 hours. The  observation time was  72 hrs. No erythema or edema were observed in any animal after 24 and 72 hrs at the shaved skin. Therefore in this study 2-hydroxypropyl methacrylate is not irritating to skin according to CLP regulation EC 1272/2008 and UN-GHS requirements.

Supporting information is available from Rohm & Haas (1982) which has not been reported in detail. HPMA was tested in a primary skin irritation test to rabbits to Draize method. 6 New Zealand White rabbits were exposed to undiluted HPMA on the shaved and shaved + scarified skin under occlusive conditions for 24 hours. The  observation time was  72 hrs. 2/6 animals showed means response  scores for erythema of 2 and 3.5, respectively after 24 and 72 hrs.  Mean erythema scores in 4/6 animals were 0. One erythema was not fully reversible within 7 days. Mean edema scores were  detected in 3/6 animals after 24 and 72 hrs with 2, 2.5 and 3 respectively. 3/6 animals showed no erythema. All edema were reversible within 7 days. Therefore in this study HPMA is not irritating to skin according to CLP regulation EC 1272/2008 and UN-GHS criteria.

Eye irritation

In the key study (Röhm, 1977) HPMA 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 were treated with 0.1 ml of the undiluted test substance and were observed for 7 days. HPMA produced corneal opacity scored 1 in 5/6 animals which was fully reversible within 4 days in all animals. One animal showed conjunctival redness scored 2. Iritis and chemosis were < 1 or < 2, respectively in all other animals. The study was reevaluated according to GHS criteria and CLP regulation EC 1272/2008.  The substance is irritating to eyes, Category 2B (GHS criteria) and Category 2, H319 (EU regulation 1272/2008, CLP criteria).

Supporting information is available from Rohm & Haas (1982) which has not been reported in detail. HPMA was tested in an eye irritation test acc. "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics'' (1959), the US Association of Food and Drug Officials (APDO). 0.1 ml undiluted test material was applicated directly onto the cornea. The eyes were not  washed. Effects in 5/6 animals were fully reversible within 7 days. In one animal very slight corneal effects (10 of max. 80 scores) persited on day 21. This effect is expected to be caused by direct application or lesion at observation. 

Respiratory irritation

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

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

• HPMA has a relatively low vapour pressure;


• HPMA 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 HPMA;


• 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 HPMA. 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

HPMA was found to be not irritating to the skin of rabbits according to CLP or UN-GHS classification criteria.

HPMA is regarded as mildly irritating to eyes based on studies in rabbits. The substance is irritating to eyes (CLP category 2; mildy irritating/ Category 2B according to UN-GHS).

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.