Registration Dossier

Administrative data

Description of key information

Overall, studies of HEMA in experimental animals and case reports in workers have provided only equivocal to weak evidence of sensitization potential. Nonetheless, for purposes of classification and labeling, HEMA should be considered to have skin sensitization potential.

No data are available to indicate that HEMA has respiratory sensitization potential.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
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: Basic data are given.
Qualifier:
according to
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 group
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
Remarks:
Migrated information
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:

Results of several dermal sensitization assays in experimental animals and in human subject case studies have been reported for HEMA. The SIDS Initial Assessment Report (2001) for HEMA concluded that:

‘Animal studies suggest HEMA is a weak skin sensitizer in guinea pigs giving variable (mixed) results depending on the protocol. Positive reactions were shown only with injection of Freund’s adjuvant but not by topical application alone. Whether or not this chemical induces skin sensitization in humans is equivocal; mixed results are reported in the literature on dental clients. Based on human patch test results, HEMA has sensitizing properties and HEMA has potential for cross-reaction with other (meth)acrylates.’

 

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. However, Clemmensen (1985) reported that 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.

Human case reports of skin sensitization to HEMA have been published. Despite negative or weak sensitizing potential demonstrated in animal experiments, there are significant numbers of reports of experiencing sensitization reactions. At least two reports [Mathias, 1979] [Kanerva: 1991] dealt with cases where the cause of sensitization appeared to be HEMA. However, many other studies dealt with subjects who had developed skin sensitization supposedly caused by exposure to agents containing HEMA. Authors of the reports generally concluded that cross-reaction may be operating in patch tests and skin sensitization potential of HEMA may be low to negligible.

 

Sandberg and Dahlgren (2006) reported on the immunological effects of HEMA in mice exposed by skin painting. A 50% solution of HEMA in vehicle was painted onto the dorsal surface of the ears of female BALB/c mice twice per week for six weeks. Production of the cytokines interleukin IL-2, IL-4, IL-6, IL-10 and interferon-γ were assessed by enzyme-linked immunosorbent assay. In a separate experiment, cytokine production was followed after subcutaneous injection of HEMA. Animals painted with HEMA in vehicle had a higher production of IL-6 by anti-CD3ε – stimulated lymph node cells and suppressed production of IL-10 by spleen cells compared to vehicle-treated mice. An injection of 20 μmole HEMA caused an increased production of IL-6 while an injection of 40 μmole HEMA reduced IL-6 and IL-10 production.

  

Sporadic case reports indicate a positive patch test reaction to HEMA when applied to symptomatic patients. Individually each of these reports is considered to be of low reliability; however collectively they provide evidence that those with jobs related to dentistry may develop into symptomatic patients who show positive challenge test results to this substance.

 

Goon et al (2006) provided results of a retrospective survey of all persons tested in dental patient and dental personnel series in southern Sweden. Among a total of 1632 patients, 2.3% of dental patients and 5.8 % of dental personnel tested positive in the methacrylate category of substances. The most common allergen for both groups was HEMA followed by ethylene glycol dimethacrylate (EGDMA) and methyl methacrylate. The allergens were applied in small Finn chambers at concentrations of 2% in petrolatum. Tests were applied to the upper part of the bak and left for 48 hours. Scores were read on day 3. 4, 7 according to ICDRG criteria.A total of 48 people (30 patients and 18 dental personnel) reacted to methacrylates, and of these, 47 had positive patch tests to HEMA. Of the 47 responding to HEMA, 30 had simultaneous positive reactions to EGDMA. The authors concluded that if only HEMA had been used for screening, all of the sensitive individuals would have been detected. Further, reading sites only on day 3 and not day 7 would have caused 17% of those sensitive to HEMA not to have been identified. This study indicates that between 2-6% of the subjects included in the study at the clinic responded to challenge with HEMA. This prevalence, however, should not be confused with expectations for the general population because the cohort being studied was preselected to be individuals already responding with skin reactions to some agent in their environment.

 

Isaksson et al (2005) reported on the time course of allergic reaction to HEMA and EGDMA in 11 patients known to be sensitized to the material. Test material of varying concentrations (2, 0.2, 0.02, 0.002 % HEMA in petrolatum) was applied to the filter paper of van der Bend chambers and applied to the upper back of patients. Tests were applied to the upper part of the back and left for 48 hours. Scores were read on days 3. 4, 7, 10, 14, 17, 21, 24, and 28 using ICDRG criteria. The authors noted that for HEMA, 25 allergic readings were recorded with 21 in the first week, 2 new reactions after 10 days and 12 reactions persisting after 4 weeks.


Respiratory sensitisation

Endpoint conclusion
Additional information:

Migrated from Short description of key information:
No data are available to indicate that HEMA has respiratory sensitization potential.

Justification for classification or non-classification

Overall, studies of HEMA in experimental animals and case reports in workers have provided only equivocal to weak evidence of sensitization potential. Nonetheless, for purposes of classification and labeling, HEMA should be considered to have skin sensitization potential.