Registration Dossier

Administrative data

Description of key information

OECD Adverse Outcome Pathway (2014)

Adverse outcome

Human data: Skin patch test data indicate that MMA is a contact sensitiser in humans with indication of a weak potency based on low prevalence in relevant cohort studies. 
Animal data (Guinea pig): inconsistent results from various test methods; mainly positive in studies with concentrations indicate that MMA is a weak skin sensitizer. 

Key events (KE)

Tissue response (LLNA animal data; = KE4)

- borderline effects from negative to weakly positive in guideline LLNAs according to OECD 429, 442A or 442B; e.g. weakly skin sensitising (OECD 429; Betts et al. 2006)

Protein binding/ molecular initiating event (in chemico data; = KE1)

- consistently moderate positive in DPRA assays according to OECD 442C or pre-GL studies

Keratinocyte inflammation/ cellular response (in vitro data; = KE2)

- predominantly weak positive in a KeratinoSens assay according to OECD 442D or pre-GL studies with LuSens or HaCaT

Dendritic cell activation/ cellular response (in vitro data; = KE3)

- consistently positive in a h-CLAT assay according to OECD 442E or pre-GL studies with MUSST, USENS or h-CLAT

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
Equivalent to Guideline strudy
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
As described in: Kimber I, Basketter D A. The murine local lymph node assay: a commentary on collaborative studies and new directions. Food Chem Toxicol 1992: 30: 165–169.
GLP compliance:
not specified
Type of study:
mouse local lymph node assay (LLNA)
Specific details on test material used for the study:
MMA (99.96% pure) was supplied by Lucite International UK Ltd via Cassel Works, Cleveland, UK.
Species:
mouse
Strain:
CBA/Ca
Sex:
not specified
Details on test animals and environmental conditions:
- Young adult CBA/Ca mice (Harlan, Bicester, Oxfordshire, UK)
- Age: 8–12 weeks
- Housing: metal cages
- Food: SDS PCD pelleted diet; Special Diets Services Ltd, Witham, UK)
- Water: ad libitum.
-Temperature: 22 +/- 3°C
- Relative humidity: 50 +/-20%
- Lightning: 12 hr light/dark cycle.
Vehicle:
other: acetone or acetone/olive oil (4:1 v/v)
Concentration:
0, 10, 30, 50 75, and 100% (neat)
No. of animals per dose:
4 per group
Details on study design:
Groups of mice were exposed topically on the dorsum of both ears to 25 µl of various concentrations of chemical, or to the same volume of vehicle alone, daily for 3 consecutive days. Five days after the initiation of exposure, all mice were injected intravenously via the tail vein with 20 µCi of [3H] methyl thymidine in 250 µl of phosphate buffered saline. Five hrs later, mice were killed and the draining auricular lymph nodes were excised and pooled for each experimental group. A single-cell suspension of lymph node cells (LNC) was prepared; approximately 12 hr later, incorporation of [3H]TdR was measured and a stimulation index relative to the concurrent vehicle-treated control value was derived.
Positive control substance(s):
other: 2,4-Dinitrochlorobenzene
Statistics:
The estimated concentration of chemical required inducing an SI of 3 relative to concurrent vehicle treated controls, or EC3 value, was derived by linear interpolation of dose–response data.
The EC3 value was calculated by interpolating between 2 points on the SI axis, one immediately above, and the other immediately below, the SI value of 3.
Positive control results:
Positive control: 2,4-Dinitrochlorobenzene (DNCB), Vehicle: Acetone/Olive Oil):
Conc (% w/v) SI
0 1
0.01 1.4
0.025 2.2
0.05 4.0
0.1 9.8
0.25 16.2
Parameter:
SI
Value:
1.4
Test group / Remarks:
10 % (w/v)
Remarks on result:
other: Vehicle: acetone
Parameter:
SI
Value:
2.3
Test group / Remarks:
30 % (w/v)
Remarks on result:
other: Vehicle: acetone
Parameter:
SI
Value:
2
Test group / Remarks:
50 % (w/v)
Remarks on result:
other: Vehicle: acetone
Key result
Parameter:
SI
Value:
4.4
Test group / Remarks:
75 % (w/v)
Remarks on result:
other: Vehicle: acetone
Key result
Parameter:
SI
Value:
7.3
Test group / Remarks:
100 % (w/v)
Remarks on result:
other: Vehicle: acetone
Parameter:
SI
Value:
1.5
Test group / Remarks:
10 % (w/v)
Remarks on result:
other: Vehicle: acetone/olive oil
Parameter:
SI
Value:
1.5
Test group / Remarks:
30 % (w/v)
Remarks on result:
other: Vehicle: acetone/olive oil
Parameter:
SI
Value:
1.5
Test group / Remarks:
50 % (w/v)
Remarks on result:
other: Vehicle: acetone/olive oil
Key result
Parameter:
SI
Value:
4.4
Test group / Remarks:
75 % (w/v)
Remarks on result:
other: Vehicle: acetone/olive oil
Key result
Parameter:
SI
Value:
3.6
Test group / Remarks:
100 % (w/v)
Remarks on result:
other: Vehicle: acetone/olive oil
Key result
Parameter:
EC3
Value:
ca. 60
Test group / Remarks:
Vehicle: acetone
Key result
Parameter:
EC3
Value:
ca. 90
Test group / Remarks:
Vehicle: acetone/olive oil
Cellular proliferation data / Observations:
see table below

Desintegrations per minute (dpm)
Conc. (% w/v) MMA, vehicle acetone MMA, vehicle acetone/olive oil DNCB/ pos. Ctrl., vehicle acetone/olive oil
0 137 243 609
0.01 ND ND 839
0.025 ND ND 1352
0.05 ND ND 2455
0.1 ND ND 5971
0.25 ND ND 9843
10 205 341 ND
30 312 363 ND
50 274 369 ND
75 605 513 ND
100 (neat) 999 874 ND
Stimulation Index (SI)
Conc. (% w/v) MMA, vehicle acetone MMA, vehicle acetone/olive oil DNCB/ pos. Ctrl., vehicle acetone/olive oil
0 1.0 1.0 1.0
0.01 ND ND 1.4
0.025 ND ND 2.2
0.05 ND ND 4.0
0.1 ND ND 9.8
0.25 ND ND 16.2
10 1.5 1.4 ND
30 2.3 1.5 ND
50 2.0 1.5 ND
75 4.4 2.1 ND
100 (neat) 7.3 3.6 ND
Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
In this local lymphnode assay methyl methacrylate attained the criteria of Skin sens Category 1 B
Executive summary:

In an mouse local lymphnode assay (Betts 2006) methyl methacrylate was tested at concentrations of 10; 30; 50; 75 and 100 % in two different vehicles (acetone and acetone/olive oil). EC50 values were 50 % (acetone) and 90 % (acetone/olive oil). In this study methyl methacrylate is a weak skin sensitizer and attained in this study the criteria of skin sens category 1 B.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

General introduction to sensitisation

The capacity of MMA to induce sensitization is directly related to its metabolism and reactive chemistry. The general metabolic pathway for MMA consists of ester hydrolysis to methacrylic acid and methanol, a process catalyzed by carboxylesterase enzymes, which are further metabolized to carbon dioxide and water. Hydrolysis and further metabolism of MMA occur rapidly following exposure as discussed in the chapter “Toxicokinetics”, based on animal in vivo and human in vitro data. 

Another potentially important metabolic pathway for MMA and related esters involves reaction with tissue nucleophiles via Michael addition on Cβof the α,β-unsaturated carboxyl group. Increased urinary excretion of thioethers and depletion of hepatocyte GSH have been documented after exposure to MMA as indication of the conjugation with glutathione (GSH) prototype for such reactions. However, the electrophilic activity of methacrylate esters, as reflected by GSH conjugation, is less than that of corresponding acrylate esters, as shown in Borak, et al. 2011 (therein Table 1, see attachment). The electrophilic reactivity of low-molecular-weight molecules is an important aspect of their ability to act as sensitizers. In skin sensitization studies, a key early step in the process leading to sensitization is the formation of covalent adducts with a carrier protein, thereby forming an antigenic hapten-protein complex. Accordingly, electrophilic reactivity also serves as a predictor of sensitization potential. Michael acceptor electrophiles, such as MMA and related esters, are generally predicted to be strong sensitizers, but there is a broad spectrum of reactivity across esters (see again Borak, et al). 

The hydrophobicity (i.e., Log P) of individual molecules is a second factor that impacts their ability to react covalently with the nucleophile groups of carrier proteins. It has been estimated that sensitization potential is about twice as dependent on electrophilic reactivity as hydrophobicity (Roberts et al., 2008). In general, the Log P of methacrylate and acrylate esters increases as the length of their alkyl side chains increase. Because of its relatively low electrophilic reactivity and relatively low Log P as contrasted with other methacrylate and acrylate esters, one would expect that MMA has comparatively low sensitizing potential. 

Hydrolysis of MMA reduces its sensitization potential because, under physiological conditions, methacrylic acid is not electrophilic or protein reactive as shown in vivo (as discussed by Borak et al. 2011).The same is true for methanol as other primary metabolite. These findings suggest that hydrolysis is the principal pathway of MMA metabolism, that the hydrolysis is a detoxification process for the sensitisation potential of MMA, and that electrophilic reaction via Michael addition plays only a minor role and seems to occur only at high tissue concentrations. 

 

Skin sensitisation

The skin sensitization potential was assessed following the considerations of the OECD guidance “The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins” (2012*). The adverse outcome itself can be assessed with the help of human data or animal data with guinea pigs, last in well-established but disputable test systems from an animal welfare perspective. Thus, test systems were developed following the 3R principle to investigate the key events for skin sensitization and have been already validated under OECD or are in progress. There is common understanding especially for the in chemico and in vitro test methods that these are individually not adequate for use as stand-alone methods for the hazard assessment, despite various achievements, so that various defined weight-of-evidence approaches are currently in discussion.

For all key aspects of skin sensitisation, reliable data are available, especially as MMA was partially subject of OECD validation studies.

 

Adverse outcome

Human data

Numerous case reports of skin sensitisation exist from certain occupational environments, where frequent and prolonged unprotected skin contact with monomer containing mixtures was common practice. Repeated exposure to undiluted MMA may lead to skin sensitisation in susceptible persons. The available data revealed extensive variation between the reports cited with respect to the number of subjects in whom a positive response was observed as a function of those tested. In fact, the prevalence was found to vary between studies from 0% to 16% (see table below

). According to Kimber & Pemberton (2014), "the higher prevalence rates were reported in

those studies where relatively small numbers of patients with dermatitis had been referred to clinic. The corollary was that much lower prevalence rates were observed among larger cohorts, buteven in those cases it could be argued that the figures obtained are an over-estimation of the frequency with which skin sensitisation develops among populations exposed to MMA. The data of Pflug (Pflug, 1995, 2000) were considered to perhaps provide the most accurate reflection of the prevalence of sensitisation to MMA in the dental industry (values of between 0.25% and 0.378%), although even in these reports there is possibly some over-estimation of true rates of sensitisation to MMA (Betts et al., 2006; Pflug, 1995, 2000). The conclusion drawn at that time was that, although there was no doubt that MMA is a contact allergen, the available evidence from predictive test methods indicated relatively weak skin sensitising potential. The data available from reports of skin sensitisation to MMA among exposed human population was considered to be consistent with that conclusion (Betts et al., 2006). It is, of course, important to consider whether there are any other data that have become available regarding human skin sensitisation to MMA since publication of the Betts et al. article (Betts et al., 2006). Little new information has emerged that is relevant to the prevalence of sensitisation to MMA, or to its sensitising potency. ... Based on all available data it is concluded that MMA is a contact allergen, but displays weak skin sensitising potential. The relatively low frequency of sensitisation among those exposed to MMA is consistent with that conclusion."

In the absence of any other data that informs understanding of human skin sensitisation to MMA there is no reason to revise the conclusions published in Kimber & Pemberton (2014).

Animal data in guinea pigs

There is a great number of reliable studies available to assess the skin sensitising potential of MMA. The variety of used test methods is large, providing positive and negative results in almost equal proportions. Nevertheless, in the most common test systems at least one positive test result can be found.

 

Key events (KE)

Tissue response (LLNA animal data; = KE4)

The LLNA is generally considered as appropriate test system for a more precise view on the potential for skin sensitisation due to the studied dose relationships, so that in a weigh-of-evidence approach this line of evidence is considered with a rather high impact. Six reliable LLNAs are available following the respective OECD guidelines OECD 429, 442A or 442B. The results are relative consistently showing borderline effects close to the criteria threshold of the respective test method, but with four being negative and two being weakly positive. Thus, MMA is considered as having a weak potential in these test systems.

 

Protein binding/ molecular initiating event (in chemico data; = KE1)

A few reliable DPRA studies are available according to OECD guideline 442C. The results are consistently moderate positive with cysteine depletion being stronger than cysteine depletion. Thus, MMA is considered as having a moderate potential in these test systems.

Keratinocyte inflammation/ cellular response (in vitro data; = KE2)

MMA was weakly positive in a KeratinoSens assay according to OECD 442D, while other test methods showed variable results with MMA in pre-GL studies (LuSens positive; HaCaT positive and negative). Thus, MMA is considered as predominantly weak positive in these test systems.

Dendritic cell activation/ cellular response (in vitro data; = KE3)

MMA was tested consistently positive in a h-CLAT assay according to OECD 442E and also in pre-GL studies with various test methods (MUSST, USENS or h-CLAT). Thus, MMA is considered as positive in these test systems; a discrimination of the potency of substances is currently not possible for these methods.

 

in silico data

Two commercial QSAR systems were used to evaluate the sensitising potential of MMA and provided inconsistent results (Kimber 2019*): DEREKTM predicted MMA to have a ‘plausible’ skin sensitisation alert whereas ‘plausible’ was defined as ‘the weight of evidence supports the proposition’ (of skin sensitising activity). The skin sensitising potential of MMA was derived from the presence of an alpha/beta-unsaturated ester. With TIMES-SS however, MMA was negative. Accordingly, Kimber (2019) concluded that "Data obtained using 2 QSAR methods (DEREKTMand TIMES-SS) were less encouraging and failed to reflect results recorded with in vivo or in vitro test methods, or with available human data.”

Irrespective of the inconclusive results for MMA, the role of SAR analyses for the identification of sensitizers remains limited.

Conclusion

The overall picture from all lines of evidence (physico-chemical properties, toxicokinetic information, human data, in vivo animal data on guinea pigs and mice, in vitro data on several key events of the AOP of this hazard, and in silico data) indicates that MMA is a skin sensizier of weak potency.

* OECD (2012). The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins, Part 1: Scientific Evidence. Series on Testing and Assessment, No.168, May 2012

* Kimber I. (2019). The activity of methacrylate esters in skin sensitisation test methods: A review. Reg Tox Pharm 104, June 2019, 14-20

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Prevalence of MMA Sensitisation: Case Reports and Other Data

Test Group (selection criteria)

Total no. or no. tested

No. tested positive

Incidence (%)

Reference

Potential bias

comments

dental technicians and students (with and without exposure to MMA, no details reported)

175

0

0

Marx et al., 1982

Bias-negative: possibly no history of exposure to MMA

Rem.: small cohort

dental technicians inwho are members of the Employer's Liability Insurances Association BGFE, Berufsgenossenschaft Feinmechanik & Elektrotechnik, Germany (~ 95 % of the workforce in that field in)

No. of applications due to recurrent, severe skin disease (BK 5101)

83191

85238

86102

73871

66696

65419

66412

195

206

200

209

214

247

194

0.23

0.24

0.23

0.28

0.32

0.38

0.29

BGFE, 1995

BGFE, 1996

BGFE, 1997

BGFE, 1998

BGFE, 1999

BGFE, 2000

BGFE, 2001

(all: personal communication)

Bias-small

(Two effects balance each other - not everyone is expected to apply (negative bias) but cases with allergies against metals or other chemicals in the field are also included (positive bias))

Rem.: Probably the most reliable estimate

patients with dermatitis with previous contact with (meth)acrylates (dental products, adhesives, ptinting agents, photopolymers, plastics) ((meth,)acrylate allergy suspected, no further details)

82

1

0.8

Guerra et al. (1993)**

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

patients with dermatitis (suspected of (meth)acrylate allergy; no further details)

1161

9

0.8

Schnuch (1997)

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

patients with dermatitis (suspected of (meth)acrylate allergy; no further details)

4221

51

1.2

Schnuch (1996)

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

patients with dermatitis (suspected of (meth)acrylate allergy; no further details)

4900

3080

4099

5812

4427

 

1.4

1.2

1.6

1.4

1.0

Pratt et al. (2004)

Marks et al.(1995, 1998

and 2003)

Zug (2009)

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

patients with dermatitis with previous contact with (meth)acrylate (no further details)

352

17

4.8

Tucker and Beck (1999)

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

patients with dermatitis with previous contact with (meth)acrylate (no further details)

271

20

7.4

Kanerva et al. (1997)

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

dental technicians with dermatitis, (details re. Exposure to MMA not reported)

72

9

13

Schnuch and Geier (1994)

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

1619 patients with contact dermatitis (23 (meth)acrylate-exposed persons were tested, no further details)

23

3

13

Kiec-Swierczynska (1996)

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

dental technicians (with dermatitis, details re. Exposure to MMA not reported)

93

17

16

Peiler et al., 1996

Bias-positive: patients of dermatologists or dermal clinics are a cohort pre-selected for having a problem with the skin

* This reference and all other ones below look at patients, i.e. cohorts which are more or less selective towards the occurrence of dermatitis, all persons without skin problems have no reason to go to a dermatologist and are so inadvertently excluded from the study

 ** Betts et. al. (2006) Skin sensitization potency of methyl methacrylate in th elocal lymph node assy: a comparison with guinea-pig data and human experimente, Contact dermatitis 2006: 55: 140 -147 cited wrongly: A printer was sensitized against methacyl methacrylate instead of patients working with dental products or adhesives.


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

A general introduction to the sensitisation potential is given above in the chapter “Skin Sensitisation” above. 

For this human health hazard, no defined test strategy exists in the REACh context for the time being. Thus, a scientifically valid weigh-of-evidence (WoE) approach has to be applied. For MMA and this hazard, the respective WoE consists of below described lines of evidence. Each line of evidence has been discussed in detail by Borak et al. 2011 and the subsequent, unpublished update for new data until 2020 (both attached). The respective summaries are presented here.

Metabolism

Specific to respiratory effects and potential sensitization, it is important to understand that high level exposure to MMA vapours are known to cause inflammatory reactions in the respiratory tract due the rapid, carboxylesterase-driven hydrolysis in these tissues to the corrosive and cytotoxic metabolite methacrylic acid (see chapters Toxikokinetics and Repeated dose - inhalation plus Chan et al. 2008). Thus enzymatic hydrolysis can be understood as weakly toxificating process for the irritative potential of MMA to the respiratory tract, eventually appearing with some delay, while these inflammatory reactions should not be misinterpreted as adverse outcome of a sensitizing process. This information is important for a scientifically valid classification of the findings described below, especially those made in humans.

 

In silico

A limited number of SAR studies have considered the contact and respiratory sensitization potential of MMA, providing an inconsistent picture from negative to positive potential. Beyond those being reliable, methacrylate esters including MMA were found to have a weak potential either due to the absence of a second reactive functional group (when compared with other LMW substances) or due to a reduced electrophilic reactivity caused by the methyl group on the α-carbon of the acrylate double bond (when compared with acrylate esters).

Although the number of reliable SAR studies is limited, they provide a weight of evidence that MMA does not cause respiratory sensitization. However, the role of SAR analyses for the identification of sensitizers remains limited; it is currently not sufficient to be regarded as “a standalone tool for hazard identification”.

 

Animal data

No data available for MMA specifically for respiratory sensitization. Moreover, as role of animal data for the identification of respiratory sensitizers is in general limited, there is no data gap identified which could improve the quality of the hazard assessment.

Animal testing with MMA specific to sensitization is restricted to skin sensitization and is described above, indicating a maximum weak sensitizing potential.

 

Human data

There is a relatively large number of human cases in literature which claim a relation between occupational MMA exposure and asthma or asthma-like symptoms. However, with increasing depth of analysis, significant limitations of each of these claims became apparent.

The final outcome of the above analysis is that, with sufficient scientific evidence, MMA has the potential to provoke respiratory irritation in pre-existing asthma cases. Furthermore, no proven case has been described for the time being which provides sufficient evidence that MMA is the biunique causative agent for the developmental of occupational asthma.

From the mentioned limitations, the most frequent ones are, on a case-by-case level

-         Lack of details in the medicinal reporting;

-         Lack of rigor in the medicinal diagnosis;

-         Weak plausibility of MMA vapour exposure being the causative agent of the symptoms;

-         Unclarity on mean and peak MMA exposure levels during work tasks and, if relevant, during diagnosis like specific challenge; and

-         Disregard of the irritant properties of MMA.

On a superordinate level, further important, but rarely considered confounding factors are

-         Impact of the relatively high background level of asthmatics and people with hyperreactive airways (e.g., 8-10% asthmatics in the EU);

-         MMA and other methacrylate esters were inappropriately grouped together with acrylate and cyanoacrylate esters just by chemical analogy;

-         Late Asthmatic Responses (LAR), seen in specific inhalation challenge (SIC) tests, are not a reliable, stand-alone indication that MMA or other methacrylates have the potential to cause immune-mediated asthmatic; and

-         insufficient implementation of existing risk reduction measures as indicated by an accumulation of claimed cases in certain industry sectors (e.g. Dental, Surgery, Cosmetics) while other industry sectors with high MMA exposure (e.g. in PMMA cast sheet plants) demonstrate a sufficient implementation by an absence of cases.

Finally, it is notable that despite the very large and increasing numbers of MMA-exposed workers worldwide (e.g. 15.000 workers in the primary industries worldwide in the early 2010s; > 400.000 dental assistants in the US or ca. 40.000 dental technicians and assistants in France at that time; Borak et al. 2011, UNPPD, 2013 , Onisep, 2018) the number of claimed cases of MMA-related occupational asthma is relatively low, especially when comparing again the background level of pre-existing hypersensitivity.

The role of human data for the identification of respiratory sensitizers has in general the highest impact on the hazard assessment. For the weight-of-evidence approach on MMA this line of evidence is basically relevant, while in absence of robust data showing clear evidence for a respiratory sensitization there is only weak evidence for a relevant potential of MMA. Instead, much stronger evidence has been identified that MMA has the potential to provoke respiratory irritation in pre-existing asthma cases – which is not relevant for classification as respiratory sensitizer.

 

Overall summary

In absence of clear key studies or key information, a weight-of-evidence assessment is required to answer the question whether there is an additional risk for respiratory sensitisation of handling MMA which must be addressed with an additional classification, additional safety measures and/or modified occupational exposure levels.  

The weight of evidence, considering experimental and observational lines of evidence, leads to the conclusion that MMA is not a respiratory sensitizer. However, there is more than sufficient evidence that MMA has the potential to provoke respiratory irritation, especially in individuals with pre-existing asthma. Existing safety measures are sufficient for safe handling of MMA if they were fully implemented. Details of this weight-of-evidence approach are attached to this endpoint summary. 

 

Reference list

Borak J, Fields C, Andrews LS and Pemberton MA: Methyl methacrylate and respiratory sensitization: A Critical review; Critical Reviews in Toxicology. 41(3): 230–268, 2011

Chan K, O’Brien O’Brien PJ.(2008). Structure-activity relationships for hepatocyte toxicity and electrophilic reactivity of alpha,beta unsaturated esters, acrylates and methacrylates. J Appl Toxicol. 28:1004–1015

Roberts DW, Aptula AO, Patlewicz G, et al.: Chemical reactivity indices and mechanism-based read-across for non-animal based assessment of skin sensitisation potential. J Appl Toxicol 28:443-454, 2008

Onisep (Office national d'information sur les enseignements et les professions) (2018): Job description “Assistant/e dentaire”; www.onisep.fr/content/download/462388/9999764/file/assistant(e) dentaire.pdf

UNPPD, Union Nationale Patronale des Prothésistes Dentaires (2013): https://www.unppd.org/

Justification for classification or non-classification

Skin Sensitization

Based on the relative consistent outcome of various valid studies on methyl methacrylate covering the complete adverse outcome pathway for skin sensisation according to OECD, it is considered that the substance comprises a potential for skin sensitisation and has therefore to be classified accordingly. While MMA is classified with Skin sens 1, H317 according to the requirements of Regulation (EC) 1272/2008, Annex VI in the EU (harmonized classification), many studies indicate a weak potency of MMA so that a subcategorisation into Cat 1B would be justified. This is in line with OECD (2018;

Report of the validation study of the Local Lymph Node Assay BrdU-FCM (LLNA: BrdU-FCM) test method. Series on Testing and Assessment No. 283, ENV/JM/MONO(2018)1) declaring MMA as weak or borderline skin sensitizer.

--

Respiratory Sensitization

Based on the available data there is no convincing evidence that MMA is a causative agent for occupational asthma/ respiratory sensitisation. 

With sufficient scientific evidence however it can be assessed that MMA has the potential to provoke respiratory irritation, especially in individuals with pre-existing asthma or hyperreactive airways. This hazard is considered with the classification STOT SE 3 (respiratory tract), see the respective chapter.

This assessment is in line with all scientific reliable assessments of the recent past:

-         EU Risk Assessment (2002; “…no convincing evidence that methyl methacrylate is a respiratory sensitiser in humans... possible non-specific asthmatic responses due to respiratory tract irritation cannot be excluded and labelling with R 37 “(for respiratory irritation)” is sufficient for the protection of humans.”Furthermore,”there is a need for limiting the risks of MMA concerning skin sensitisation and respiratory tract irritation at several workplaces in the chemical industry, industrial area and skilled trade and during use of casting resins”)

-         SCOEL (2005; “MMA is clearly a sensory irritant towards the respiratory tract and in the majority of these cases "asthmatic" respiratory responses have been attributed to exposure to transiently high concentrations of MMA that may have resulted in respiratory irritation in individuals with normal airway responsiveness, or perhaps in some cases with preexisting, generally hyperreactive airways. There are also other features that confound the interpretation of the experiences reported in some of these cases. Overall, there is no convincing evidence that methyl methacrylate is a significant inducer of asthma in humans”)

-         Borak et al. (2011; “the weight of evidence, both experimental and observational, argues that MMA is not a respiratory sensitizer. However, there is more than sufficient evidence that it can act as a human respiratory irritant and as such, it may also cause irritant-induced occupational asthma. The distinction between the two mechanisms (i.e., irritant versus sensitizer) has important implications for workplace engineering controls and public health. Without regard to underlying mechanisms of injury, our review also suggests important actions that should be taken to prevent adverse effects of “MMA exposure,” especially among workers in secondary MMA industries.”)

 

ECHA’s endpoint specific guidance (2017) states very clear that misinterpretation and wrong classification is not warranted: “In case there is evidence available that the substance induces asthma-like symptoms by irritation only, these substances should not be considered as respiratory sensitisers”. In addition, partially observed unspecific responses in hyperreactive individuals do not trigger a classification according to CLP.

Therefore, a classification for respiratory sensitisation is considered as not justified.