Dimethyl itaconate

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2013-11-06 to 2013-12-10

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study according guidelines (OECD 405, EU Method B.5, EPA OPPTS 870.2400, FAMIC) under GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: FAMIC

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

DMI

IUPAC Name:

DMI

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): DMI
- Expiration date of the lot/batch: 2014-08-15
- Storage condition of test material: at room temperature in the dark

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan, Horst, The Netherlands; Charles River France, L’Arbresle Cedex, France
- Age at study initiation: between 12 and 24 weeks old
- Weight at study initiation: at least 1.5 kg
- Housing: individually in labeled cages with perforated floors (Ebeco, Germany, dimensions 67 x 62 x 55 cm) and shelters (Ebeco, Germany, dimensions 40 x 32 x 23 cm)
- Diet (e.g. ad libitum): pelleted diet approximately 100 g per day
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): 15 room
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 2013-11-06 to 2013-11-14

Test system

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 mL

Duration of treatment / exposure:

at least 24 hours following instillation

Observation period (in vivo):

1, 24, 48 and 72 hours after instillation

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

SCORING SYSTEM:
CORNEAL IRRITATION
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity (may include slight dulling of normal luster) 0
Scattered or diffuse areas of opacity, details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Nacreous area, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4

Area of cornea involved:
No ulceration or opacity 0
One quarter or less but not zero 1
Greater than one quarter, but less than half 2
Greater than half, but less than three quarters 3
Greater than three quarters, up to whole area 4

IRIS
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia,
or injection, any of these or combination thereof, iris still reacting to light
(sluggish reaction is positive) 1
No reaction to light, hemorrhage, gross destruction (any or all of these) 2

CONJUNCTIVAL IRRITATION
Redness (refers to palpebrae and sclera, excluding cornea and iris):
Blood vessels normal 0
Some blood vessels definitely hyperaemic (injected) 1
Diffuse, crimson color, individual vessels not easily discernible 2
Diffuse beefy red 3

Chemosis (refers to lids and/or nictitating membranes):
No swelling 0
Any swelling above normal (includes nictitating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids more than half closed 4

Discharge:
No discharge (may include small amounts observed in inner canthus of normal animals) 0
Any amount different from normal and/or lacrimation 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs (considerable area around the eye) 3


TOOL USED TO ASSESS SCORE: 2 % fluorescein in water, where standard lighting was considered inadequate for observing minor effects, eye examinations were performed using an ophthalmic examination lamp.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

animal: 11

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 2

Irritation parameter:

iris score

Basis:

animal: 11

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 3

Irritation parameter:

conjunctivae score

Basis:

animal: 11

Time point:

other: Mean 24, 48 and 72 hours

Score:

0.7

Max. score:

1

Reversibility:

fully reversible within: 72 h

Results 4

Irritation parameter:

chemosis score

Basis:

animal: 11

Time point:

other: Mean 24, 48 and 72 hours

Score:

0.3

Max. score:

1

Reversibility:

fully reversible within: 48 h

Results 5

Irritation parameter:

cornea opacity score

Basis:

animal: 89

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 6

Irritation parameter:

iris score

Basis:

animal: 89

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 7

Irritation parameter:

conjunctivae score

Basis:

animal: 89

Time point:

other: Mean 24, 48 and 72 hours

Score:

0.7

Max. score:

1

Reversibility:

fully reversible within: 72 h

Results 8

Irritation parameter:

chemosis score

Basis:

animal: 89

Time point:

other: Mean 24, 48 and 72 hours

Score:

0.3

Max. score:

1

Reversibility:

fully reversible within: 48 h

Results 9

Irritation parameter:

cornea opacity score

Basis:

animal: 93

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 10

Irritation parameter:

iris score

Basis:

animal: 93

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Results 11

Irritation parameter:

conjunctivae score

Basis:

animal: 93

Time point:

other: Mean 24, 48 and 72 hours

Score:

0.7

Max. score:

1

Reversibility:

fully reversible within: 72 h

Results 12

Irritation parameter:

chemosis score

Basis:

animal: 93

Time point:

other: Mean 24, 48 and 72 hours

Score:

0.3

Max. score:

1

Reversibility:

fully reversible within: 48 h

Any other information on results incl. tables

Table 1: Individual eye irritation scores

				Cornea				Iris		Conjunctivae
Animal	Time after dosing			Opacity (0-4)	Area (0-4)	Fluor area (%)^2		(0-2)		Redness (0-3)	Chemosis (0-4)	Discharge (0-3)
11^1	1 hour			0	0			0		2	2	1
	24 hours			0	0	0		0		1	1	1
	48 hours			0	0	-		0		1	0	0
	72 hours			0	0	-		0		0	0	0
89	1 hour			0	0			1		2	1	1
	24 hours			0	0	0		0		1	1	1
	48 hours			0	0	-		0		1	0	0
	72 hours			0	0	-		0		0	0	0
93	1 hour			0	0			0		2	2	1
	24 hours			0	0	0		0		1	1	1
	48 hours			0	0	-		0		1	0	0
	72 hours			0	0	-		0		0	0	0

Applicant's summary and conclusion

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

Based on the study results. Dimethyl itaconate (DMI) does not have to be classified and has no obligatory labelling requirement for eye irritation according to the CLP-GHS.

Executive summary:

The study was carried according to OECD TG 405, EC B5, EPA OPPTS 870.2400 and FAMIC Guidelines, including the most recent revisions. Single samples of 0.1 mL of Dimethyl itaconate (DMI) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation. Instillation of the test substance resulted in irritation of the conjunctivae, which consisted of redness, chemosis and discharge. The irritation had completely resolved within 72 hours. Iridial irritation grade 1 was observed in one animal and resolved within 24 hours. Based on these results, Dimethyl itaconate (DMI) does not have to be classified and has no obligatory labelling requirement for eye irritation according to the: Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011), Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.