Dimethyl itaconate

Endpoint summary

Description of key information

Skin irritation: irritating, OECD TG 439; Eurlings / 2015 / Reconstructed Human Epidermis Test Method & Key / Heppenheimer / 2011 / skin corrosion / Human Skin Model Test
Eye irritation: not irritating, OECD TG 405; Zmarowski / 2013 / rabbit
Respiratory irritation: no data available

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Experimental starting date: 12 October 2015, Experimental completion date: 19 October 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Valid and conclusive guideline study under GLP; Relevant and adequate for the endpoint

Qualifier:

according to guideline

Guideline:

EU Method B.46 (In Vitro Skin Irritation: Reconstructed Human Epidermis Model Test)

Version / remarks:

Official Journal of the European Union No. L142; Amended by EC No. 640/2012 OJ No. L193, 20 July 2012 ( (EpiSkin™ model))

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)

Version / remarks:

adopted 26 July 2013 (EpiSkin™ model)

Deviations:

no

GLP compliance:

yes

Species:

human

Strain:

other: not applicable, in vitro test using Reconstructed Human Epidermis (EpiSkin™ model)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Not applicable, as a reconstructed human epidermis model was used in vitro.
- EPISKIN Standard Model™ (EPISKIN-SMTM, 0.38 cm², Batch no.: 15-EKIN-041). This model is a three-dimensional human epidermis model, which consists of adult human-derived epidermal keratinocytes which have been seeded on a dermal substitute consisting of a collagen type I matrix coated with type IV collagen. The keratinocytes were cultured for 13 days, which results in a highly differentiated and stratified epidermis model comprising the main basal, supra basal, spinous and granular layers and a functional stratum corneum.
- Source: SkinEthic Laboratories, Lyon, France
- Preincubation (tissues): On the day of receipt the tissues were transferred to 12-well plates and preincubated with prewarmed Maintenance Medium for approximately 27 hours at 37 °C

ENVIRONMENTAL CONDITIONS
All incubations, with the exception of the test item incubation of 15 minutes at room temperature, were carried out in a controlled environment:
Temporary deviations from the temperature, humidity and CO2 percentage may occur due to opening and closing of the incubator door.
Based on laboratory historical data these deviations are considered not to affect the study integrity.
- Temperature (°C): 37.0±1.0 °C (actual range 36.5 - 37.3 °C; Temperature was continuously monitored throughout the experiment.
- Humidity (%): 80 - 100 % (actual range 70 - 91 %; Humidity was continuously monitored throughout the experiment.
- Air: The test atmosphere contained 5.0 ± 0.5 % carbon dioxide; The CO2 percentage was monitored once on each working day.
- Photoperiod: The test was conducted in the dark.

Type of coverage:

open

Preparation of test site:

other: None, not required for use of the EPISKIN Standard Model. The liquid test item was applied directly on top of the tissue.

Vehicle:

unchanged (no vehicle)

Controls:

other: negative (Phosphate Buffered Saline, PBS) and positive (Sodium Dodecyl Sulphate, CAS 151-21-3) controls with 3 tissues each

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 25 µL of the liquid test item was applied (on 0.38 cm²)
- Concentration: The liquid test item was applied undiluted

VEHICLE
No vehicle was used

Duration of treatment / exposure:

15 min of treatment at room temperature, then rinsing, followed by 42 h of post-incubation period at 37 °C

Observation period:

After a 42 hour post-exposure incubation period, determination of the cytotoxic (irritancy) effect was performed. The incubation for the cell viability measurement was made during 3 h.

Number of animals:

The test was performed on a total of 3 tissues (i.e. three replicates of treatment, negative and positive control)

Details on study design:

TEST SITE
- Area of exposure: In the in vitro study 0.38 cm² of the skin tissue (EPISKIN Standard Model™) was exposed in well plates
- % coverage: The skin tissue (EPISKIN Standard Model™) was completely covered by the liquid test item, no wrap was therefore used

REMOVAL OF TEST SUBSTANCE
- Washing: After exposure the skin tissue was thoroughly rinsed to remove the test item and transferred to fresh medium.
- Time after start of exposure: 15 min of treatment at room temperature, then rinsing

SCORING SYSTEM: Cell viability (cytotoxicity) was measured after rinsing, followed by 42 h of post-incubation period at 37 °C. Cytotoxicity is expressed as the reduction of mitochondrial dehydrogenase activity measured by formazan (CAS 504-65-4) production from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT, CAS 298-93-1) at the end of the treatment by OD570 (optical density at 570 nm) determination. Non-irritancy has to be considered according to the test guideline if the treatments show > 50 % of the mean viability of the negative controls.

Irritant / corrosive response data:

The test item was checked for colour interference in aqueous conditions and possible direct MTT reduction by adding the test item to MTT medium. Because no colour changes were observed it was concluded that it did not interact with the MTT endpoint.
The mean absorption (Optical Density) at 570 nm (OD570) measured after treatment and in controls are presented in Table 1. Table 2 shows the mean tissue viability obtained after 15 ± 0.5 minutes treatment with the test item compared to the negative control tissues.
The positive control had a mean cell viability after 15 ± 0.5 minutes exposure of 12 %. The absolute mean OD570 of the negative control tissues, which was within the laboratory historical control data range (Table 3). The standard deviation value of the percentage viability of three tissues treated identically with the positive control was less than 14 %. Thus the test system functioned properly.
The relative mean tissue viability obtained after 15 ± 0.5 minutes treatment with the test item compared to the negative control tissues was 14 %. Since the mean relative tissue viability was below 50 % it is considered to be irritant or corrosive.

Table 1: Mean absorption

Sample	Optical density at 570 nm [1]
	A	B	C	Mean±SD
Negative control	0.917	0.742	0.977	0.878±0.122
Test item	0.127	0.096	0.145	0.123±0.025
Positive control	0.077	0.134	0.110	0.107±0.028

OD = Optical Density

SD = Standard deviation

The triplicate exposures are indicated by A, B and C.

In the above table the values are corrected for background absorption (0.0415). Isopropanol was used to measure the background absorption.

Table 2: Mean tissue viability

Sample	Mean tissue viability [% of control]
Negative control	100
Test item	14
Positive control	12

In Tables 2 and 3 Skin irritation is expressed as the remaining cell viability after exposure to the test item.

Table 3: Historical Control Data for in vitro Skin Irritation Studies in the Test Laboratory

	Optical density at 570 nm [1]		Viability [%]
	Negative control	Positive control	Positive control
Range	0.576 – 1.352	0.020 – 0.408	2.1 – 43.0
Mean	1.03	0.14	14.8
SD	0.15	0.11	10.7
n	91	91	108

SD = Standard deviation

n = number of observations

The above mentioned historical control data range of the controls were obtained by collecting all data over the period of March 2012 to March 2015.

Interpretation of results:

other: positive answer, indicating either corrosive (UN-GHS Cat. 1) or irritant (UN-GHS Cat. 2) properties

Remarks:

Criteria used for interpretation of results: OECD GHS

Conclusions:

In a valid in vitro Reconstructed Human Epidermis test using the EpiSkin™ assay the test item gave a positive answer, which indicates that it is either corrosive (US-GHS Cat. 1) or irritant (US-GHS Cat. 2).

Executive summary:

The in vitro irritation potential of the test item Dimethyl itaconate (CAS 617-52-7, purity 99.6 %) to Reconstructed Human Epidermis tissues (RHE, EpiSkin™ model) was investigated in a GLP-compliant study according to the OECD TG 439 (2013) and EU B.46 (2012) protocols. The experiment can be considered valid, relevant and adequate for final conclusion on the presence or absence of corrosive (UN-GHS category 1) and/or irritant (UN-GHS category 2) properties. Therefore it can be deemed conclusive for presence of absence of non-irritancy and was rated „reliable without restrictions“, i.e. “Klimisch 1” according to the scale of Klimisch et al. (1997).

The test was performed in three replicates employing tissues treated with undiluted test item, Phosphate Buffered Saline (PBS) serving as negative control and 5 % Sodium Dodecyl Sulphate (SDS, CAS 151-21-3) serving as positive control. The equal volume of twenty five μL was added into 12-well plates on top of the skin tissues. After the exposure period of 15 ± 0.5 minutes at room temperature, the tissues were washed with PBS to remove residual test item. After rinsing the cell culture inserts were each dried carefully and moved to a new well on 2 mL pre-warmed maintenance medium until all tissues were dosed and rinsed. Subsequently the skin tissues were incubated for 42 hours at 37 °C. After incubation, cell culture inserts were dried carefully to remove excess medium and were transferred into a 12-well plate prefilled with 2 mL Methylthiazoletetrazolium (MTT, CAS 298-93-1)-medium (0.3 mg/mL). The tissues were incubated for 3 hours at 37 °C. After incubation the tissues were placed on blotting paper for drying. Epidermis was separated from the collagen matrix and both parts were placed in prelabeled microtubes and extracted with 500 μL isopropanol (CAS 67-63-0). Tubes were stored refrigerated and protected from light for 72 hours. The amount of extracted formazan (CAS 504-65-4) was determined spectrophotometrically at 570 nm in duplicate. Cell viability was calculated for each tissue as a percentage of the mean of the negative control tissues.

The test item was checked for colour interference in aqueous conditions and possible direct MTT reduction by adding the test item to MTT medium. Because no colour changes were observed it was concluded that it did not interact with the MTT endpoint.

The positive control had a mean cell viability of 12 % and the absolute mean Optical Density at 570 nm (OD570) of the negative control tissues (set to 100 %), which was within the laboratory historical control data range. The standard deviation value of the percentage viability of three tissues treated identically with the positive control was less than 14 %. Thus the test system functioned properly.

The relative mean tissue viability of the test item treatments compared to the negative control tissues was 14 %. Since the mean relative tissue viability was not equal to or above 50 % it cannot be regarded as an a non-irritant in agreement with the test guidelines.

In result and according to CLP (considered up to the 7th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU) this study indicates that the test item is either corrosive (Cat. 1) or irritant (Cat. 2). To finally conclude on classification a further study designed to distinguish between corrosive and irritant effects (e.g. OECD TG 431) is required.

• Klimisch HJ, Andreae M, Tillmann U (1997). A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data. DOI 10.1006/rtph.1996.1076 PMID 9056496 Regul Toxicol Pharmacol 25:1-5.

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:

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: FAMIC

Deviations:

no

GLP compliance:

yes

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

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.

Irritation parameter:

cornea opacity score

Basis:

animal: 11

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Irritation parameter:

iris score

Basis:

animal: 11

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

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

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

Irritation parameter:

cornea opacity score

Basis:

animal: 89

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Irritation parameter:

iris score

Basis:

animal: 89

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

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

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

Irritation parameter:

cornea opacity score

Basis:

animal: 93

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

Irritation parameter:

iris score

Basis:

animal: 93

Time point:

other: Mean 24, 48 and 72 hours

Score:

0

Max. score:

0

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

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

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

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

- skin irritation/corrosion:

Three fully reliable in vitro studies are available: The Eurlings (2015) and Verbaan (2010) studies for skin irritation and the Heppenheimer (2011) study for skin corrosion.

The Eurlings (2015) and Verbaan (2010) studies were conducted according to OECD TG 439 and GLP using the EpiSkin™ Standard model. The experiments were conducted using two different purity grades (99.6 and only 98.5 % purity, respectively). In this test system skin irritation is expressed as the remaining cell viability after exposure to the test substance. The relative mean tissue viability obtained after 15 minutes treatment with Dimethyl itaconate (DMI) compared to the negative control tissues was 14 and 7 %, respectively. This result supports the assumption that impurities may trigger the irritancy of the submission item as the more pure test item showed the lower effect. Since the mean relative tissue viability for Dimethyl itaconate (DMI) was below 50 % after 15 minutes treatment it is considered to be irritant or corrosive as the test design used discriminates skin irritants (Category 2) from substances not classified for skin irritation (no Category) under CLP. However, it cannot distinguish skin irritants (Category 2) from skin corrosives (Category 1). The latter discrimination needs to be addressed with an in vitro skin corrosion test (ECHA 2015a p 275 & decision logic p 284, ECHA 2015b p 185-6), which is available.

The Heppenheimer (2011) study was conducted according to OECD TG 431 and GLP using Human Skin Model. In this test system skin corrosion is expressed as decrease in cell viability below defined threshold levels at specific exposure periods. After exposure to the test item DMI Proviron the relative absorbance values decreased to 81.8 % after 3 minutes. After the 1 hour exposure relative absorbance values were reduced to 24.5 %. Both values did not exceed the threshold for corrosivity of 50 % for the 3 minutes exposure and 15 % for the 1 hour exposure. Therefore, the test item was not considered to be corrosive according to UN GHS / EU CLP Cat.1 / DSD (67/548/EEC).

• ECHA European Chemicals Agency (2015a). Guidance on the Application of the CLP Criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. Version 4.1. Self-published, Helsinki, Finland, in June. ISBN 978-92-9247-413-3 Reference ECHA-15-G-05-EN. 644 p.
• ECHA European Chemicals Agency (2015b). Guidance on information requirements and chemical safety assessment. Chapter R.7a: Endpoint specific guidance. Version 4.1. Document Reference ECHA-15-G-04.1-EN. ISBN 978-92-9247-411-9. Self-published, Helsinki, Finland, in October. 495 p.

- eye irritation/corrosion:

Only one fully reliable in vivo study (Zmarowski, 2013) is available, which is regarded as key study. This study was conducted according to OECD TG 405 and GLP in three rabbits. Single samples of 0.1 mL of test item were instilled into one eye of each of three rabbits. Based on 24, 48 and 72 hours observation scores after instillation, the test item does not have to be classified for eye irritation according to CLP-GHS.

Four fully reliable supporting in vitro studies are available (Verspeek-Rip, 2012a;Verspeek-Rip, 2012b; Verspeek-Rip, 2010 and Verspeek-Rip, 2012c) conducted according to OECD TG 437 and GLP using the Bovine Corneal Opacity and Permeability test.

In these studies the clear dependence on the test item purity was observed. The BCOP studies with DMI purity above 99.1% (upper range of the declared for registration purity) showed that DMI is not corrosive or highly irritating, whereas the studies with DMI purity below 99.1% showed that the test item is corrosive or highly irritant to the eyes. Based on the irritation test in vivo (Zmarowski, 2013) it was concluded that DMI with declared for registration purity is not irritant to eye.

- respiratory irritation:

no data available

Justification for selection of skin irritation / corrosion endpoint:
All three listed in vitro studies are reliable and recognised by CLP/GHS. The Eurlings (2015) and Verbaan (2010) studies using 99.6 and only 98.5 % purity, respectively, show classifiable, but indistinguishable irritant/corrosive properties of the compound. In the Heppenheimer (2011) study the submission item (> 97 % purity) was evidenced being not corrosive to skin. The result obtained with the highest purity (Eurlings 2015) corresponds best to the marketed substance and is thus considered the key study. However the Heppenheimer (2011) study is mandatory to distinguish between irritant and corrosive effect levels. Thus it is considered a second key study.

Justification for selection of eye irritation endpoint:
For eye irritation endpoint, only this one reliable in vivo study is available.

Effects on skin irritation/corrosion: irritating

Justification for classification or non-classification

Skin irritation/corrosion:

Based on the above stated assessment of the skin irritation potential dimethyl itaconate needs to be classified as Category 2 (H315: Causes skin irritation) according to CLP (considered up to the 7th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

Table: Skin corrosion/irritation label elements for category 2 (CLP, 5th ATP, Annex I, 3.2.4.1, Table 3.2.5)

Element		Type
GHS Pictogram		GHS07 exclamation mark
Signal Word		Warning
Hazard Statement		H315: Causes skin irritation
Precautionary Statements	Prevention	P264, P280
	Response	P302 + P352, P321, P332 + P313, P362 + P364 (4th ATP change)
	Storage	none
	Disposal	none

Eye irritation/corrosion:

Based on the above stated assessment dimethyl itaconate is not irritating to eye according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

Respiratory irritation:

As no data on respiratory irritation is available for dimethyl itaconate a classification is not possible according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.