Isobutyl methacrylate

Endpoint summary

Description of key information

i-BMA is a slight to moderate skin irritant.
i-BMA a slight eye irritant. 
i-BMA vapour is expected to induce irritation of the respiratory tract at high concentrations.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

The skin irritation was assessed in a weight of evidence approach based on three studies with isobutyl methacrylate and two valid studies with the structurally similar n-butyl methacrylate[A1] 

(Similarity is based on the closely related molecular structure, identical metabolic pathways with common or similar metabolites and half-lives (Jones, 2002) as well as in similar physico-chemical properties. (i-BMA/n-BMA - molecular weight: 142.2g/mol/142.2 g/mol; boiling point: 155 °C/163 °C; vapour pressure: 2.11 hPa/2.1 hPa; water solubility: 0.47 g/l @ 20 °C/0.36 g/l@°25 °C; log Pow: 2.95/3.0).

Only the data for the shaved, intact skin were used for evaluation. In studies carried out with more than 3 animals both approaches, the overall mean score and the average score determined per animal, were used for evaluation.

1. Isobutyl methacrylate, skin irritation test (Sterner/Stiglic, 1977), 2 hours exposure time. Test acc. appraisal of the safety of chemicals in foods, drugs and cosmetics, FDA (Draize)(1959) Application: 2 hours, occlusive (shaved and shaved/scarified) Six New Zealand White rabbits were assigned to study. In order to investigate the reproducibility of the effects, each rabbit had two separate dose sites (shaved and shaved/scarified), which were treated with 0.5 ml of undiluted test material. In addition, two untreated areas (shaved and shaved/scarified) were used as the control. Only reactions which were different from those of the control were evaluated as positive reactions. For each treated dose site, 0.5 ml of undiluted test material was soaked onto a gauze patch (approx. 6 cm²) which was held in place with adhesive tape on the shaved and shaved/scarified skin of the test animals. The animals were fixed in a holding device and their bodies were wrapped in a rubberised cloth for 2 hours. After this time, the dressing and adhesive tape were removed and the local reactions were examined. Twenty-four and 72 hours after application, the examinations were repeated. The test result is the average of the scores of the 24- and 72-hour examination.

Results: Shaved, intact skin: Mean erythema scores (24+72 h) per animal were 0.5 (three animals), 1.5 (two animals) and 2.0 (one animal). Evaluated with the second approach the overall mean erythema score was 1.8. Mean scores (24+72 h) per animal were 0 (two animals), 0.5 (two animals), 1.0 (two animals). Overall mean score (24+72 h) was 0.5. Some erythema and scores persisted at point 72 h. As the exposure time was too short it cannot be excluded that the substance has a higher irritating potential.

 

2.[A2] In another study conducted by the same study directors (Sterner/Stiglic) and an exposure time of 24 h the irritating potential was slightly higher. Isobutyl methacrylate, skin irritation test acc. to ‘Appraisal of the safety of chemicals in foods, drugs and cosmetics’ six New Zealand White rabbits were restrained in stocks and the fur removed by clipping. Half of the exposed area was abraded and the other half remained intact. 0.5 ml of isobutyl methacrylate was applied to shaved intact and abraded skin sites and covered with a patch. Two areas remained untreated as control. The animals were fixed and covered with a rubber cloth for 24 hours. Then the patches were removed and the local reactions were evaluated after 24 and 72 hours in contrast to the control.

Results:

Shaved, intact skin: Mean erythema scores (24+72 h) per animal were 0.5 (two animals), 1.0 (two animals) and 1.5 (two animals). Evaluated with the second approach the overall mean erythema score was 0.917. Meanscores (24+72 h) per animal were 0 (two animals), 0.5 (one animal), 1.0 (three animals). Overall meanscore (24+72 h) was 0.667. Some erythema and scores persisted at point 72 h. As the exposure time was too short it cannot be excluded that the substance has a higher irritating potential.

3. Isobutyl methacrylate: Skin irritation test acc. to Federal Hazardous Substances Labelling Act Regulations, Section 191.11, published in the Federal Register (USA)-29 F.R. 13009, (1964) (Poole 1980b). Six NZ White rabbits were restrained in stocks and the fur removed by clipping. Half of the exposed area was abraded and the other half remained intact. 0.5 ml of isobutyl methacrylate was applied to the shaved intact and abraded skin sites and covered with surgical gauze. The area was then wrapped with impervious tape and a stockinette sleeve. Test material remained in contact for 24 hrs and then removed. Irritation scores were determined at 24 and 72 hours after patch removal.

Result:

Shaved, intact skin: Mean erythema scores (24+72 h) per animal were 1.0 (two animals) and 2.0 (four animals). Evaluated with the second approach the overall mean erythema score was 1.83. Mean scores (24+72 h) per animal were 1.0 (two animals), 2.5 (one animal) and 3.0 (three animals). Overall mean oedema score (24+72 h) was 2.25. Erythema and scores persisted at point 72 h. The exposure time was higher (24 h instead of 4 h) and the observation time lower (only 72 h) so that reversibility could not be demonstrated.

4. n-Butyl methacrylate (Zechel 1982): In a study comparable to OECD 404, 0.5 ml n-Butyl methacrylate was applied to the intact skin of rabbits under occlusive and semi occlusive conditions for one and 4 hours. Animals were observed 24 h, 48 h, 72 h and 7 days after patch removal.

Result:

Semi occlusive, 4 hours exposure: Mean erythema scores (24+48+72 h) per animal were 0.66 (one animals), 1.0 (three animals), 1.33 (one animal) and 1.66 (one animal). Evaluated with the second approach the overall mean erythema score was 1.11. Mean scores (24++48+72 h) were 0 for all animals. All erythema scores were fully reversible within 7 days.

5. n-Butyl methacrylate (Poole 1980a): Six NZ White rabbits were restrained in stocks and the fur removed by clipping. Half of the exposed area was abraded and the other half remained intact. 0.5 ml of n-butyl methacrylate was applied to the shaved intact and abraded skin sites and covered with surgical gauze. The area was then wrapped with impervious tape and a stockinette sleeve. Test material remained in contact for 24 hrs and then removed. Irritation scores were determined at 24 and 72 hours after patch removal.

Result:

Shaved, intact skin: Mean erythema scores (24+72 h) per animal were 1.5 (one animal), 2.0 (three animals) and 2.5 (two animals). Evaluated with the second approach the overall mean erythema score was 2.08. Meanscores (24+72 h) per animal were 1 (one animal), 1.5 (two animals), 2.0 (one animal), 2.5 (one animal) and 3.0 (one animal) . Overall mean oedema score (24+72 h) was 1.83. Erythema andscores persisted at point 72 h. The exposure time was higher (24 h instead of 4 h) and the observation time lower (only 72 h) so that reversibility could not be demonstrated.

By design, the observation period of the studies with isobutyl methacrylate was too short to observe full recovery of the animals and also the duration of exposure is either shorter or longer than the current guideline value. By analogy to n-BMA it is assumed, that all effects would have resumed by day 14. Consequently, on balance and in the purpose of precautionary principle, i-BMA is considered as irritant to skin.

 Please add further information, why similarity is given (e.g. physicochemical properties of the structurally similar substance… see http://echa.europa.eu/documents/10162/13632/information_requirements_r6_en.pdf R.6.2.3.1Step 2: Data gathering for the analogues).

 Would you mind to adjust the order and make it similar to related table or adjust the table.

Eye irritation

1.Isobutyl methacrylate: In a study following an FDA guideline (Draize protocol) isobutyl methacrylate (0.1 ml) was instilled into the right eye of six New Zealand White rabbits (Poole, 1980b). The lids were then gently held together for one second. The test eyes were not washed out following the instillation. The left eye remained untreated for control. The eyes were examined at 24, 48 and 72 hours from beginning of test. Eye irritation was scored for signs of corneal damage (density, area), iris reaction and lesions of the conjunctivae (erythema, chemosis and discharge). Additionally, the cornea was examined with the aid of fluorescein after recording the observations at 24 hours. There were no signs of damage to iris or cornea.Initially, all rabbits showed signs of slight to moderate erythema and chemosis of the conjunctiva[A2] . While the chemosis had almost completely resolved by 72 h the erythema had improved but was not completely reversible at that time. In this study i-BMA is considered as slightly irritating to eyes. (Mean conjunctiva scores over a period of 24, 48 and 72 h: 0.33-2.0, mean chemosis scores: 0-1.33).

2. Isobutyl methacrylate: In an OECD 405 guideline study Schreiber G (1988) isobutyl methacrylate (0.1 ml) was placed into the conjunctival sac of the right eye of three New Zealand White rabbits. The lids were then gently held together for one second. The test eyes were not washed out following the instillation. The left eye remained untreated for control. The eyes were examined at 1, 24, 48 and 72 hours as well as 8 days from beginning of test. Eye irritation was scored for signs of corneal damage (density, area), iris reaction and lesions of the conjunctivae (erythema, chemosis, discharge). Additionally, the cornea was examined with the aid of fluorescein after recording the observations at 24 hours. One hour after dosing, one animal exhibited slight conjunctival redness, chemosis and discharge. Only erythema persisted for 24 hours. At 48 hours following dosing all signs of irritation had resolved. The remaining animal showed no signs of irritation at any time during the test. (Mean conjunctiva score (redness) over a period of 24, 48 and 72 h: 0-0.33) Isobutyl methacrylate is considered as not irritating to eyes.

In studies with the structurally close related substance n-butyl methacrylate by the same study directors with the same study design irritation scores and reversibility were similar to isobutyl methacrylate.

(Similarity is given in the molecular structure as well as in physico-chemical properties.
i-BMA/n-BMA - molecular weight: 142.2g/mol/142.2 g/mol; boiling point: 155 °C/163 °C; vapour pressure: 2.11 hPa/2.1 hPa; water solubility: 0.47 g/l @ 20 °C/0.36 g/l@°25 °C; log Pow: 2.95/3.0).

 

3. n-Butyl methacrylate: In an OECD 405 guideline study, 0.1 ml n-butyl methacrylate was placed into the conjunctival sac of the right eye of three New Zealand White rabbits (Schreiber and Wodtke, 1988). The lids were then gently held together for one second. The test eyes were not washed out following the instillation. The left eye remained untreated for control. The eyes were examined at 1, 24, 48 and 72 hours as well as 8 days from beginning of test. Eye irritation was scored for signs of corneal damage (density, area), iris reaction and lesions of the conjunctivae (erythema, chemosis and discharge). Additionally, the cornea was examined with the aid of fluorescein after recording the observations at 24 hours. One hour after dosing, two animals exhibited slight conjunctival redness, chemosis and discharge, which persisted for 24 hours in one animal. The second animal also exhibited conjunctiva erythema at 24 hours af
ter dosing. At 48 hours following dosing all signs of irritation had resolved. The remaining animal showed no signs of irritation at any time during the test. (Mean conjunctiva scores and oedema scores over a period of 24, 48 and 72 h: 0-0.33) n-Butyl methacrylate is considered as slightly irritating to eyes.

4. n-Butyl methacrylate: In addition, in an FDA Draize test(Poole LJ, 1980a).[A3] 0.1 ml undiluted n-BMA was applied into the conjunctival sac of one eye of six New-Zealand white rabbits, respectively. The ocular reactions were observed at 24, 48 and 72 hours after instillation. Observation time was not prolonged. Slight to well defined redness of the conjunctivae was observed in four of six animals. There were no signs of damage to iris or cornea (scores: 0). Mean scores over 24, 48 and 72 hours were 0-1.67 for erythema and 0-1.33 for chemosis n-Butyl methacrylate is considered as slightly irritating to eyes.

Respiratory tract irritation

No respiratory irritation was found in the olfactory region in an acute inhalation study after 6 hours whole body exposure with 200 ppm isobutyl methacrylate in rats, but signs of respiratory irritation were observed at higher concentrations in an acute inhalation toxicity study and in a 28 days repeated dose inhalation study (952 ppm and higher), both performed with the close structural analogue, n-butyl methacrylate.

By analogy to the structurally very closely related isomer n-butyl methacrylate, isobutyl methacrylate is considered to be irritating to the respiratory tract.

Based on results of studies with exposures higher than 200 ppm isobutyl methacrylate has to be classified as irritant to the respiratory tract STOT single exposure Cat. 3, H335 according to Regulation EC No 1272/2008 (CLP Regulation).

Corrosion

i-BMA is not corrosive to skin or eyes. Since the primary acid metabolite, MAA, is corrosive to skin and eyes and this hazard is not observed in the irritation studies with the parent C1-C8 methacrylate esters, localised metabolism and associated local effects due to high concentrations of the MAA metabolite are not of concern for irritation effects.

 

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: slightly irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin irritation

The skin irritation was assessed in a weight of evidence approach based on three studies with isobutyl methacrylate and two valid studies with the structurally similar n-Butyl methacrylate[A1] 

Only the data for the shaved, intact skin were used for evaluation. In studies carried out with more than 3 animals both approaches, the overall mean score and the average score determined per animal, were used for evaluation.

For isobutyl methacrylate 3 studies with only 72 hours observation time are available. All studies were carried out with 6 animals that both approaches were used for evaluation. In two studies (Sterner) with an exposure time of two and 24 hours all irritation scores were < 2.3 but reversibility could not be demonstrated. In the third study (Poole 1980 b) mean scores in 4/6 animals were > 2.3. Overall score in six animals was 2.25. In this study the exposure time was 24 h and the observation time only 72 h.

 Compared to available studies with n-butyl methacrylate in a study carried out by the same study director (Poole 1980 a) and the same study design erythema scores were slightly above the results with iso-butyl methacrylate and scores were slightly below them.

In a further study (Zechel 1982) with n-butyl methacrylate all scores were < 2.3 and were fully reversible within 7 days.

By design, the observation period of the studies with isobutyl methacrylate was too short to observe full recovery of the animals and also the duration of exposure is either shorter or longer than the current guideline value. By analogy to n-Butyl methacrylate it is assumed, that all effects would have resumed by 14 d.

Hence, isobutyl methacrylate is classified as a skin irritant (R38/H315 and skin irritation Cat. 2) according to DSD and CLP Regulation criteria, respectively.

Eye irritation

Two reliable studies acc. FDA (Draize protocol) and OECD 404 are available with isobutyl methacrylate and also with the structurally related n-butyl methacrylate. The studies were carried out in a similar fashion. No signs of damage to iris or cornea were observed in all studies. Highest mean erythema score (score 2) was observed in 1/6 animals with isobutyl methacrylate and in 1/6 animals (score 1.67) with n-butyl methacrylate. Full reversibility was shown in OECD 404 studies after 8 days. Based on the available data i-BMA doesn't fullfil the criteria for classification. Nevertheless, the CLP Annex VI entries still specify i-BMA as eye irritant, category 2.

Irritation to the respiratory tract

No respiratory irritation was found in the olfactory region in an acute inhalation study after 6 hours whole body exposure with 200 ppm isobutyl methacrylate in rats, but signs of respiratory irritation were observed at higher concentrations in an acute inhalation toxicity study and in a 28 days repeated dose inhalation study (952 ppm and higher), both performed with the close structural analogue, n-butyl methacrylate.

By analogy to the structurally very closely related isomer n-butyl methacrylate, isobutyl methacrylate is considered to be irritating to the respiratory tract.

Based on results of studies with exposures higher than 200 ppm isobutyl methacrylate has to be classified as irritant to the respiratory tract STOT single exposure Cat. 3, H335 according to Regulation EC No 1272/2008 (CLP Regulation).