2-hydroxyethyl methacrylate

Endpoint summary

Description of key information

Skin sensitisation

The skin sensitization potential of HEMA is clearly documented by human and animal data which however does not allow robust subcategorization beyond the exclusion of a high potency.

Respiratory sensitisation

Insufficient evidence to consider HEMA as a cause of respiratory sensitisation or OA (Weight-of-Evidence assessment)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Documentation sufficient for assessment.

Qualifier:

according to guideline

Guideline:

other: Magnusson and Kligman (1970)

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

The test was performed in 1985 before LLNA-method has been developed.

Species:

guinea pig

Strain:

other: Ssc:AL

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Statens Seruminstitut, Cpenhagen, Denmark
- Weight at study initiation: 300- 350 g
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22 deg C
- Humidity (%): 50-70%
- Air changes (per hr): 8
- Photoperiod (hrs dark / hrs light): 21.00 to 09.00 hours

Route:

intradermal and epicutaneous

Vehicle:

other: soybean oil; soybean oil + 2-butanone; sterile water

Concentration / amount:

1% soybean oil, 25% soybean oil, 25% soybean oil+2-butanone, 1% aqueous, 10% aqueous, 25% aqueous

Route:

epicutaneous, occlusive

Vehicle:

other: soybean oil; soybean oil + 2-butanone; sterile water

Concentration / amount:

1% soybean oil, 25% soybean oil, 25% soybean oil+2-butanone, 1% aqueous, 10% aqueous, 25% aqueous

No. of animals per dose:

1% soybean oil - 20
25% soybean oil - 12
25% soybean oil+2-butanone - 10
1% aqueous - 12
10% aqueous- 12
25% aqueous - 12

Details on study design:

Induction: 
Day 0:  3 pairs of injections; 1. 2 x 50 uL suspension of FCA in sterile water (1:1)
 2. 2 x 50 uL test substance 1-25 % in different vehicles
 3. 2 x 50 uL test substance in FCA (1:1)            
Day 7:  approx. 250 mg 10 % sodium dodecyl sulphate in petrolatum, 24 h, uncovered           
Day 8:  400 uL test substance undiluted, occlusive, 48 h
Challenge: Day 21: 25 uL test preparation, 25 - 100 % in different vehicles  24 h

Challenge controls:

Control and test animals received identical treatment.

Positive control substance(s):

yes

Remarks:

Cyclophosphamide

Reading:

1st reading

Group:

other: test chemical (intradermal induction 1% soybean oil)

Dose level:

challenge 100%

No. with + reactions:

0

Total no. in group:

20

Reading:

1st reading

Group:

other: test chemical (intradermal induction 25% soybean oil)

Dose level:

challenge 25% pet.

No. with + reactions:

10

Total no. in group:

12

Guinea pigs exhibited none or slight responses to sensitization with low concentration of 2-Hydroxyethyl methacrylate in the guinea pig maximization test, while 60 -100 % reacted to high concentrations regardless of the vehicle used in induction. The major determinant of the frequency of response was the concentration used for intradermal induction. Positive responses ranged from 0/20 to 9/12 animals.

 

Influence of vehicle and concentration on sentization to 2-hydroxyethylmethacrylate in the guinea pig maximization test

 

Intradermal induction % HEMA in	challenge
	25% pet.	25% aq.	25% sbomek	25% sbo	100%
1% sbo	0/20	nt	nt	0/20	0/20
25% sbo	10/12	9/12	10/12	8/12	4/12
25% sbomek	9/10	10/10	9/10	9/10	5/10
1% aq.	4/12	0/12	0/12	0/12	0/12
10% aq.	6/12	4/12	6/12	5/12	4/12
25% aq.	9/12	7/12	7/12	9/12	2/12

sbo = soybean oil; sbomek = soybean oil + 2-butanone (1:2, v/v); aq. = sterile water; pet. = white petrolatum

Interpretation of results:

sensitising

Conclusions:

The response of guinea pigs to HEMA in the Magnusson-Kligman protocol was highly dependent upon the concentration of HEMA in the vehicle used for intradermal injection. A low concentration of HEMA (1% in either aqueous or oil vehicle did not lead to a sensitization response while high concentrations (25%) in either vehicle did lead to a response in a large proportion of animals.

Executive summary:

Guinea pigs exhibited none or slight responses to sensitization with low concentrations or 2- hydroxyethylmethacrylate in the guinea pig maximization test, while 60-100% reacted to high concentrations regardless of the vehicle used for induction. Petrolatum, water, soybean oil and a mixture of oil and 2-butanone (sbomek) were used as vehicles for elicitation. The neat methacrylate was less effective than dilutions in any vehicle, petrolatum being the best. The major determinant of the frequency or response was the concentration used for intradermal induction. An increase in frequency and in duration of responsiveness after treatment with cyclophospliamide 2 days before challenge suggests that hydroxymethacrylate preferentially stimulates the suppressor cell function.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data are given.

Qualifier:

according to guideline

Guideline:

other: Modified Buehler

GLP compliance:

no

Type of study:

Buehler test

Justification for non-LLNA method:

an in vitro or in chemico skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available

Species:

guinea pig

Strain:

other: Pirbright; sub-strain: Hoe: DHPK (SPF- LAC.) /Boe

Sex:

male

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Lippische Versuchstierzucht
- Weight at study initiation: 226-385 g
- Housing: two animals per cage; Macrolon Plastic cages II
- Diet (e.g. ad libitum): pellets
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6-7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 deg C +/-2
- Humidity (%): 45-55%
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark; Fluorescent light, 4000 deg K, 120 Lux


IN-LIFE DATES: From: 1982-05-19 To: 1982-06-18

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.5 mL

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.5 mL

No. of animals per dose:

20- test
10- control

Details on study design:

RANGE FINDING TESTS: The highest non-irritating concentration was determined. The entire back and both sides of 4 animals were clipped one day prior to application. The following day the animals were exposed for one 6 hour period to various concentrations of the test substance. The sample was applied in four different concentrations: 100%, 75%, 50% and 25% in Aqua dest. The responses were graded at 24 and 48 hours.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 hour/exposure
- Test groups: 1; 20 animals
- Control group:1; 10 animals
- Site: left flank
- Frequency of applications: once/week
- Concentrations: 0.5 mL

B. CHALLENGE EXPOSURE
- No. of exposures: 3
- Exposure period: 6 hour/exposure
- Test groups: 1; 20 animals
- Control group: 1; 10 animals
- Site: right flank
- Concentrations: 0.5 mL
- Evaluation (hr after challenge): 24 and 48 hours

OTHER: body weights were taken at Day 0 and at the end of the entire testing period.

Challenge controls:

Previously untreated control animals from the induction phase.

Positive control substance(s):

no

Positive control results:

Not applicable

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.5 mL

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

none

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.5 mL. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: none.

Interpretation of results:

not sensitising

Conclusions:

There was no signs of erythema or edema observed during the testing period. According to the method, the test substance is considered to cause no delayed contact hypersensitivity.

Executive summary:

The determination of the delayed contact hypersensitivity was performed in two groups of male guinea pigs; the test group and a control group following a modified Buehler method. All animals gained weight satisfactorily during the observation period. No animals showed signs of erythema or edema. The test substance is considered to cause no delayed contact hypersensitivity.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

1. General introduction to sensitisation

The capacity of HEMA to induce sensitization is directly related to its metabolism and reactive chemistry. The general metabolic pathway for HEMA consists of ester hydrolysis to methacrylic acid and ethylene glycol, a process catalyzed by carboxylesterase enzymes, which are further metabolized to carbon dioxide and water, in the case of methacrylic acid, and glucose, in the case of ethylene glucose. Hydrolysis and further metabolism of HEMA occur rapidly following exposure as discussed in the chapter “Toxicokinetics”.   

Another potentially important metabolic pathway for HEMA and related esters involves reaction with tissue nucleophiles via Michael addition on C_β of the α,β-unsaturated carboxyl group. 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. The electrophilic reactivity of low-molecular-weight molecules is an important aspect of their potential to act as sensitizers. In skin sensitization studies for example, 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. 

Hydrolysis of HEMA 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). Also, ethylene glycol as other primary metabolite is not a skin sensitizer (e.g., Basketter et al. 1998). Metabolism data suggest that hydrolysis is the principal pathway of HEMA metabolism, and that the hydrolysis is basically a detoxification process for the sensitisation potential of HEMA. Electrophilic reaction via Michael addition is expected to play only a minor role and thus may explain why in human patch tests, skin sensitization occurs apparently only at high tissue concentrations.

 

2. Skin sensitisation

2.1 Dermal absorption

Heylings (2013) used a QSPeR model for whole human skin based on that described by Potts and Guy (1992) to predict the dermal penetration rate of a large number of methacrylate esters with the help of molecule size and distribution coefficient, including the hydroxyalkyl methacrylates HEMA & HPMA. As relatively small, hydrophilic esters the hydroxyalkyl methacrylates are predicted to be rapidly absorbed (HEMA: “high” relative dermal absorption with a predicted dermal flux of 151 µg/cm2/h). However, as indicated by studies summarised in CSR section 5.2 metabolism (IUCLID 7.1.1), they will be subject to hydrolysis by local esterases in the stratum corneum.

2.2. Human data

2.2.1. Type of information

The most relevant clinical studies are presented in Table 1 that is available in the attached document “Endpoint summary skin sens HEMA”. In all these studies with either consecutive or unselected patients (where allergic contact dermatitis/ACD is generally suspected for a group of patients) or selected patients (ACD specifically suspected for acrylic compounds), the diagnostic method was patch testing (human diagnostic patch test, HDPT) according to international standards by dermatologists (Johansen et al. 2015). These typically retroperspective studies can allow an assessment of the prevalence of positive reactions in unselected or selected patient groups.

Details on Case Reports on numerous single cases have been compiled in a separate document attached to this endpoint summary.

In contrast to the numerous HDPT studies and case studies, data on dermal exposure levels to HEMA is scarce.

2.2.1 Adequacy of human data

In general, HDPT studies have several limitations for classification and labelling, as stated by an OECD expert group for the assessment of human data for skin sensitisation potential (OECD TG 497, Annex 4, 2021) that lead to a nonconsideration of this study type for potency considerations:

• HDPT studies cover elicitation (response to challenge with allergen) and not induction of sensitisation.


• In the case of HDPT data, previous exposure to the chemical often cannot be established with enough certainty to evaluate its potency for induction of sensitisation; even if it is established qualitatively, exposure can almost never be quantified in a satisfying manner (there might be exceptions at the workplace, but for consumers it is practically not possible). The situation is further complicated because patients might have had contact with other chemicals cross-reacting with the chemical in question.

For this assessment here, the OECD approach was partially followed in a way that HDPT data (and related cross-sectional studies) were considered only from a qualitative perspective, i.e. not used for considerations on potency/ subcategorisation.

Most of the HDPT studies available for HEMA have several additional limitations. For example, cross-reactivity between different (meth)acrylate monomers, concomitant sensitization, as well as impurities with undeclared mixtures of monomers in preparations used at work and in test substances, make accurate mapping of contact sensitization difficult (Kanerva et al. 1994, Rustermeyer et al. 1998, Kanerva et al 1988, Wrangsjö et al 2001). In most of the clinical reports, specific exposure to HEMA in patch-tested patients, or those who tested positive to the substance, is not verified. As another example, sorting irritant from allergic reactions can be challenging and was often not described in detail. Thus, the relevance of reactions was often not proven.

Prevalence in +/-unselected patient groups/ addition of HEMA to baseline series

HEMA has been added to some of the national/ supra-national baseline series in Europe just more recently, since 2016. Before that time, studies with +/- unselected patient groups were rare. The most relevant studies of that type are briefly described below. Upfront, it has to be taken considered that patients of dermatologists or dermal clinics represent a preselected cohort (as the patient are having a problem with the skin), so that no valid assessment of actual prevalence for the total general population can be done.

Goon et al (2008) reported that after five acrylate/methacrylate allergens were included in the baseline series for at least 2 years in Malmö and Singapore, 19/2790 (0.7%) of all patients tested reacted positive for HEMA.

DeKoven et al (2017 and 2018) reported that at 13 centers in North America, a total of 4871 patients were tested in a standardized manner with a screening series of 70 allergens including HEMA between January 2013 and December 2014 and a total of 5597 patients were tested between January 2015 and February 2017. In 2013/14 128/4859 (2,63%) and between 2015 and 2017 188/5594 (3,36%) of all patients tested reacted positive to HEMA.

Stingieni et al (2019) published data of baseline testing in which routine patch testing with HEMA (2% in petrolatum) in 4025 consecutive patients (1499 men, 2526 women; mean age 47.2 years) was performed in 8 Italian dermatology departments between 11/2017 and 10/2018. Among the 4025 patch tested patients, 61 (1.5%) reacted to HEMA. In both non-occupational and occupational settings, sensitivity to HEMA was mainly caused by nail (meth)acrylates (88.9% and 64.3%, respectively), and was documented in 86.8% of females and in no males (P = 0.005).

In a further study by Rolls et al. (2019), in total 5920 patients with eczema were tested to the extended British baseline patch test series including HEMA 2% in petrolatum (pet.). Overall, 102 of 5920 (1.7%) tested positive to HEMA and 140 (2.4%) to at least one (meth)acrylate.

A prospective study on screening contact allergy to acrylic acid on 436 consecutively patch-tested patients was conducted in 3 Italian patch test clinics in January to March 2018 (Hansel et al 2020). Additional patch tests with (meth)acrylate series were performed in patients positive to acrylic acid or HEMA or with a history of (meth)acrylate allergy. Positive reactions to HEMA were observed in seven patients (1.6%).

The prevalence of positive reactions in routine testing (patients with no specific history) in the available studies so far is in the range between 0.7 and 3.4 % (mean 1.86%). It has to be taken into account, that patients of dermatologists or dermal clinics are a cohort preselected for having a problem with the skin, so that no valid assessment of actual prevalence in the general population can be done.

Prevalence in selected patient groups

Before adding HEMA to at least some of the baseline series, it was usually tested as part of specific (meth)acrylate patch test series, tested with pre-selected patients strongly based on suspected contact with acrylic compounds (women with artificial nails) or special occupational groups (dentists, dental workers, nail artists). A high number of diagnostic patch test studies on selected patients are available for this substance. The frequency of positive reactions was generally high, depending on the selection of patient groups.

Patients with suspected exposure related to nail cosmetic products (occupational and general) had the highest incidences of positive reactions to HEMA. The respective publications rarely differentiated between consumer and/or professional use so it is nearly impossible to estimate exposure levels or a reliable reference size. Compared to the professional users of artificial nail systems, the positive reactions to HEMA seem to be less common among those who are only consumers. Although the number of users is not known, the data should be interpreted in the context of the apparently widespread exposure among consumers and the number of professional users of artificial nail products (Scientific Committee on Consumer Safety, SCCS 2018).

No strict workplace studies could be identified for HEMA. However, one cross-sectional study on dental technicians, who are at risk of developing a contact allergy due to exposure to acrylic compounds at work, shares a similar design. Only the workers with skin symptoms were patch tested in this study. Frequency of positive reactions to the substance was 33% (18 of 55 patients tested; Rustemeyer & Frosch 1996). The numbers / incidences amongst dental technicians must be rated against a very high number of workers in this field. Because most of the reported cases for dental technicians were reported by IVDK database in Germany, a suitable reference is the total number of people working in this field. For Germany in 2018 total of around 64,700 dental technicians was published (Atlas Dentalstudie 2018). Between 1993 and 2015 a total number of 172 dental technicians tested positive for HEMA (Rustemeyer and Frosch 1996, Schnuch and Geier 1994, Schnuch et al. 1997/1998, Peiler et al. 2000, Wrangsjö 2001, Goon 2006, Heratizadeh et al. 2018). Related to the total number of dental technicians in Germany this is about 0.26%. This does not even take into account, that some of these individual patients were probably working outside Germany (e.g. Sweden).

Effective training and risk management programs in exposure to allergens and use of proper personal protection in dental practice and among dental students are proven to minimize development of allergies in these groups.

Evaluation of human data

Taken together each of these studies is of limited power. Bias or confounders have not been ruled out fully with reasonable confidence. Nevertheless, there is clear evidence that HEMA has the potential to cause skin sensitisation in humans.

 

 2.3 Non-human data

2.3.1 In-chemico/in-vitro

There are in-chemico and in-vitro studies available covering all three key events (KE1-3) that consistently show positive reactions in pre-guideline versions of the DPRA, LuSens and MUSST test systems (Kolle S. 2013). These studies, seen alone or as battery, do not allow a reliable conclusion on the potency.

2.3.2 Animal data

LLNA

A local lymph node assay (LLNA) is not available for HEMA

Guinea pigs

A guinea pig maximization test (GMPT) investigated the influence of concentration, vehicle, and cyclophosphamide on the skin sensitising potential of HEMA. The vehicles used for elicitation were petrolatum, soybean oil, and a mixture of soybean oil and 2-butanone (sbomek) (Clemmensen 1985). Ten to twenty guinea pigs (Scc:AL) were used per dose group. The response of guinea pigs to HEMA in the Magnusson-Kligman protocol was highly dependent upon the concentration of HEMA in the vehicle used for intradermal injection. A low concentration of HEMA (1% in either aqueous or oil vehicle did not lead to a sensitization response. Induction with 10% HEMA or greater caused a reaction in 4 to 10 guinea pigs out of 12 challenged per dose group while high concentrations (25%) in either vehicle did lead to a response in a large proportion of animals.

HEMA has been evaluated for skin sensitization using the Buehler assay in guinea pigs (Evonik Rohm, 1982). HEMA was found not to be sensitizing to skin in the Buehler assay when tested under occlusive conditions.

Other guinea pig studies (Katsuno 1995, Katsuno 1996) showed that HEMA produced positive delayed hypersensitivity reactions: 6 out of 10 albino guinea pigs induced and challenged with HEMA (100%) showed a positive reaction at 24 hours (mean response 2.4) and 5 out of 10 showed a positive reaction at 48 hours (mean response 2.2) (Katsuno 1995).

In a subsequent study of Katsuno (1996), the optimum concentration of HEMA for sensitisation and elicitation was established. It was shown that the optimum concentration to induce sensitisation was 0.2%. HEMA produced positive skin reactions only after challenge concentrations of 100% (5/5 pos. at 24 hours and 48 hours after patch removal with a mean skin response of 5.0. Challenge with HEMA concentration below 100 % (10, 25, 50%) did not produce any positive reactions.

Further not reliable or not assignable studies were briefly described in the attached document “Endpoint summary skin sens HEMA”.

2.3.2.1 Cross-reactions in animals

Cross-reactions have been described in various animal studies and are described in the attached document “Endpoint summary skin sens HEMA”.

Evaluation of hazard in animal studies

All available animal data support a weak to moderate potency in the GMPT and in the Buehler assay.

 

2.4 Comparison against the CLP criteria

Animal data

In the key study (Clemensen 1985) it was shown that high concentrations (> 10%) are required during elicitation to provoke positive reactions in the GMPT. After intradermal induction with 1% HEMA in soybean oil 0/20 animals in each group reacted positive following elicitation with 25% HEMA in pet, 25% HEMA in soybean oil or 100 % HEMA. After intradermal induction with 1% HEMA in water 4/12 animals = 30% reacted positive following challenge exposure with 25% HEMA in petrolatum while no animal reacted positive in other vehicels to 25% HEMA. . Induction with 10% HEMA caused a reaction in 30-50% guinea pigs when challenged with 25 or 100% HEMA in the various vehicles. 

Human data

Frequency

Frequencies of positive patch tests in unselected/ consecutive dermatitis patients (≥ 1.0 % (0.6 – 3.4%) for HEMA) and in selected dermatitis patients (≥ 2.0 %) indicate high frequency.

In the available cross-sectional studies on a risk occupation (mimicking a workplace study), the frequency of positive patch tests was well above the cut-off value of 1.0% (>> 1.0 % for nail care workers; >> 1.0 % for dentists/ dental workers). For more details, see attached document “Endpoint summary skin sens HEMA”.

Exposure aspects

While cross reactivity to other methacrylates is expected and methacrylates are common substances in occupational uses in dental materials, glues and several other products with skin contact, relatively high exposure is expected at concentrations > 1%, repeated exposures and numbers of can be assumed. For more details, see attached document “Endpoint summary skin sens HEMA”.

Summary

For the elicitation of skin sensitizing effects in humans by HEMA, relatively high local concentrations are required. Following CLP criteria on exposure aspects, it can be concluded that HEMA is not a high potency skin sensitizer. Following ECHA’s Guidance on the Application of CLP Criteria 2017b, a combination of a relatively high frequency of occurrence with a relatively high exposure requirement triggers a classification with Cat 1 without subcategorisation. This assessment is consistent with the legally binding classification Annex VI of CLP Regulation 1272/2008/EC.

Other EU Regulations

The use of HEMA is restricted to professional use only in the EU as of September 2021 (Commission Regulation (EU) 2020/1682 of November 12,2020 amending Annex III to Regulation (EC) No 1223/2009 of the European Parliament and of the Council on cosmetic products).

 

Additional literature

Goon AT, Bruze M, Zimerson E, Goh CL, Soo-Quee Koh D, Isaksson M (2008) Screening for acrylate/methacrylate allergy in the baseline series: our experience in Sweden and Singapore. Contact Dermatitis 59:307-313

Kanerva L. Estlander T, Jolanki R. (1994) Occupational skin allergy in the dental profession. Dermatologic Clinics 12: 517-532.

Kanerva L. (2001) Cross-reactions of multifunctional methacrylates and acrylates. Acta Odontol Scand. Oct;59(5):320-9.

Rustememeyer T, De Groot J, Von Blomberg B M E,Frosch P J. Scheper R J. (1998) Cross-Reactivity Patterns of Contact-Sensitizing Mcthacrylates. Toxicology and Applied Phrarmacology 148: 83-90.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Weight-of-Evidence assessment on the potential of HEMA and HPMA for respiratory sensitisation - summary

All available information has been systematically assessed for its evidence that supports, or contradicts, the hypothesis that HEMA and/or HPMA can cause the development of respiratory sensitisation, or occupational asthma (OA), in subjects that were not previously asthmatic. This has been done in a structured manner following CLP requirements for the classification of potential respiratory sensitizers (section 3.4.2.1.1.3.) and on the basis of the respective ECHA template for Weight-of-Evidence (WoE) assessments. The complete assessment is attached to this endpoint summary.

As first conclusion it is noted that for none of the investigated Lines of Evidence (LoEs), there is high quality information that at the same time fullfills relevant causality aspects (in terms of consistency, specificity, biologically plausibility and temporality) and, moreover, has a proper level of certainty. As consequence, none of these LoEs provides a high level of confidence for, or against, the tested hypothesis.

According to CLP criteria, human data have the highest predefined weigh in a WoE assessment and have therefore to be evaluated with special attention. The 13 potential clinical cases from the dental and cosmetic sector related to HEMA, respectively, do not fullfill CLP requirements “of reliable and good quality evidence”. For example, none of the known SIC tests (specific inhalation challenge) have been performed with the singe substance so that none of these tests can be seen as conform to guidelines. It is noted that none of these cases is directly related to respiratory exposure to HPMA, and this is the only relevant differentiation that can be made between HEMA and HPMA within the total WoE assessment. One eventual reason for that observation is that HPMA appears to be used less frequent in the relevant sectors, especially in the dental sector. Other branches of the human LoE (i.e. national health surveillance databases – no cases - & human exposure – implausible) do provide weak evidence against the tested hypothesis. Main sources of uncertainties in this LoE are A) the significant co-exposure in the occupational setting as well in performed SIC tests, including co-exposure to the acknowledged asthmagen Glutaraldehyde in the dental sector; B) the confounding clinical history of all but one patients and C) the inconsistent immunological pattern. In summary, no relevant evidence for the hypothesis is derived from human data that these substances can cause the development of respiratory sensitisation. This is especially true for HPMA in absence of relevant clinical cases.

An earlier assessment, that are also based on human data and that thus have also a relatively high predefined weigh in a WoE assessment, came to the same conclusion, on a however weaker data base.

Other lines of evidences provide either weak evidence for[1] or against[2] the hypothesis that both substances can cause the development of respiratory sensitisation. In addition, all those LoEs are generally afflicted with significant uncertainties so that they are considered as of minor relevance for the WoE assessment.

The conclusion drawn from these analyses, with focus on human data, indicate that there is insufficient evidence to implicate HEMA or HPMA as a cause of respiratory sensitisation or OA. Therefore, there is no basis for classification as respiratory sensitisers under EU CLP, which is widely consistent UN GHS.

 

[1] Such LoEs were structural alerts, QSAR, ADME, other relevant hazards, in vitro/ ex vivo and in vivo data

[2] Such LoEs were phys-chem properties and analogous substances

Justification for classification or non-classification

Skin Sensitisation

HEMA is classified as Skin Sensitiser Cat 1 according to CLP Annex VI (Index No. 607-124-00-X). The available data supports this classification. The data does not allow a sub-categorisation with acceptable confidence. As a consequence, HEMA has to be classified as Skin Sens. Cat 1 in the EU, and analogously under UN GHS. The corresponding hazard statement is H317: May cause an allergic skin reaction.

Respiratory Sensitisation

The conclusion drawn from comprehensive weight-of-evidence analyses, with focus on human data, indicate that there is insufficient evidence to implicate HEMA as a cause of respiratory sensitisation or occupational asthma. Therefore, there is no basis for classification as respiratory sensitiser under EU CLP or UN GHS.