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Description of key information

There are valid study data available to assess the skin sensitising potential trimethylolpropane triacrylate (TMPTA) but no information on respiratory sensitisation is available.

Studies and publications according to other protocols:

A study was conducted to assess the skin sensitisation potential of the test substance (trimethylolpropane triacrylate - TMPTA) in the guinea-pig Buehler test (Cytec, Industrial Bio-Test, 1974, Brett B.). Therefore 10 animals were insulted with a 5 h single occlusive patch containing 0.5 mL of 1% v/v (in propylene glycol) test material for a total of nine times during induction phase. Two weeks after the last exposure, the test animals and four controls were challenged with duplicate patches (both on test and virgin sites) similar to the induction phase. The application sites were graded for irritation 24 and 48 h after the initial insult, 24 h after each intermediate insult, and 24 and 48 h after challenge. Only one of the test animals showed minimal erythema during induction phase and none of the control or test animals showed any reaction after challenge. In conclusion, the test substance (trimethylolpropane triacrylate - TMPTA) was not a skin sensitiser in this guinea-pig skin sensitisation test.

The national toxicology program (NTP) conducted two further studies, a mouse ear-swelling test and a local lymph node assay. Prior to the tests a primary irritancy study of trimethylolpropane triacrylate was performed to determine the maximal no irritating and minimal irritating concentrations. Results of the irritancy study indicated that the maximal no irritating and minimal irritating doses were 0.1% and 0.25% trimethylolpropane triacrylate, respectively.

The mouse ear-swelling test was conducted with female BALB/c mice to evaluate the contact hypersensitisation of trimethylolpropane triacrylate. (Publication: NTP,Virgini, 2005). The test was conducted according to NTP protocols using 8 animals per dose. 0% (two control groups), 0.01%, 0.05%, or 0.1% (w/v) trimethylolpropane triacrylate in acetone was applied epicutaneous. In result there were no significant differences in the percentage of ear swelling were observed between the trimethylolpropane triacrylate sensitized and challenged mice and the background controls at 24 or 48 hours after dosing.

The local lymph node assay was conducted with female BALB/c mice receiving 0% (vehicle controls), 0.05%, 0.1%, or 0.25% (w/v) trimethylolpropane triacrylate in acetone dermal once per day for 3 consecutive days (Publication: NTP, Medical College Virgini, 2005). On day 5, [3H]-thymidine was intravenously injected into the tail vein. 5 hours after the injection animals were killed and lymph nodes were excised and prepared for measurement. In result the local lymph node assay indicated no significant increase in lymph node cell proliferation in mice administered trimethylolpropane triacrylate compared to that in the vehicle controls.

In a sensitisation study (Publication: 1983, Nethercott et al.), groups of 10 female albino Hartley/Dalkin guinea pigs were induced and then challenged with trimethylolpropane triacrylate according the protocol of Magnusson and Kligman. Three intradermal injections were administered to each shoulder: 0.1 mL of a 0.5% or 10% solution of trimethylolpropane triacrylate in propylene glycol; 0.05 mL Freund’s Complete Adjuvant (FCA) and 0.05 mL of a 0.5% or 10% solution of trimethylolpropane triacrylate in propylene glycol; and 0.1 mL FCA. After 1 week, 0.5% or 10% trimethylolpropane triacrylate in petrolatum was applied to the animals’ shaved shoulders, which were then wrapped for 48 hours. The animals were challenged 2 weeks after the topical exposure with skin patches of non-irritant concentrations of trimethylolpropane triacrylate for 24 hours. Four guinea pigs that were administered 0.5% trimethylolpropane triacrylate and 10 of 20 administered the 10% solution became sensitized; the intradermal sensitivity concentration for 50% of the animals was determined to be 5.4%. In result sensitising potential of TMPTA could be observed within this the guinea pig maximisation test.

In a further publication the sensitizing capacity of TMPTA was determined by the "Guinea pig maximization test" GPMT (Publication: 1980, Björkner, B.) using the protocol of Magnusson and Kligman. Therefore 24 animals were induced intradermal with 1% TMPTA in olive oil, topical with 25% in petrol and challenged with 0.5 and 0.1% in petrol. Cross reaction was tested with Penta-erythritol triacrylate (PETA) and trimethylol propane trimethacrylate (TMPTMA). 16 animals receiving 0.5% TMPTA and 6 animals receiving 0.1% TMPTA became sensitised. Cross sensitisation could be observed for PETA where 18 and 12 animals became sensitised at concentration of (0.5%) and (0,1%), respectively. No cross sensitisation to TMPTMA or Acrylic acid could be observed.

Publications of human evidence:

A sensitized subgroup of workers (working in the manufacturing of UV cured inks) was used for sensitisation patch testing (Publication: 1977 Emmett E.A. et al.,) Seven of the eight affected employees had unequivocal positive reactions to 1% trimethylol propane triacrylate in petrolatum. According to the author it is concluded that triacrylate propane triacrylate appear to be strong allergens capable of sensitizing a significant percentage of the workforce exposed to them over a relatively short period of time. Nevertheless the author hints to the possibility that some of the observed reactions represent cross reactions.

Additional in a publication (Publication: 1983, Nethercott et al.) it is reported about a human patch test with workers. Six workers received the test material (Trimethylolpropane triacrylate 0.1% in petrolatum) applied to " Al-test strips" (Hollister-Stier Ltd) that were then fixed to the upper back of each subject. Patches were removed after 48 hours. The sites were examined and scored after 30 min based on the scoring system recommended by International Contact Dermatitis Group. The sites were examined further at 72 and 96 hours. In result the patch test of the worker delivers a positive result for TMPTA for one case. This worker has oedematous or vesicular reaction after 48h and 96 hours.

A further publication compiles 10 years of patch testing with 30 (meth)acrylates (Publication: 1997, Kanerva et. al.). Altogether 275 patients were patch tested and 48 patients (11.5%) had an allergic reaction to at least 1 (meth)acrylate. For TMPTA and OTA 480 during the years 1985 -1995 243 patch tests were performed. No allergic reactions were caused trimethylolpropane triacrylate (TMPTA) or oligotriacrylate 480 (OTA 480).

 

Assessment sensitisation:

All available information is taken into account to assess the sensitising potential of TMPTA. Also useful publication was used to fill gaps of knowledge concerning the sensitising capacity.

The study conducted by Industrial BioTech 1974 must be evaluated carefully because numerous discrepancies within other studies were found during an inspection 1976 in this institute. As the study is not audited the reliability of the negative result is not ensured. But nevertheless other studies, like NTP studies, delivered also negative result. It is therefore possible that this study was conducted adequately. Against these negative results are some positive sensitisations tests reported in literature (Publication: 1980 Björkner, B.; Publication: 1983 Nethercott et al.),

But more critical concern rises from human patch test results. There are a few reports in literature available reporting about positive patch tests (of sensitized subpopulations) or cross sensitisation (e.G. Publication: 1977 Emmett E.A. et al. and Publication: 1983, Nethercott et al). This information was maybe taken into account from the NTP when developing the official classification for TMPTA. But there is also a publication from Kanerva et al. 1997 showing no allergic reactions to TMPTA when summarising 10 years of patch testing (243 patients).

As the integrated reports and publications delivers an equivocal picture of the sensitisation hazard but there is the concern left that sensitizing potential exist and as it is additionally known that also cross sensitisation to other acrylates exist the applicant assumed to follow a worst case approach. Therefore, TMPTA is considered as a sensitizer following the recommendation of the NTP. These decisions may additionally be underlined by a read across approach to TMPeoTA. TMPeoTA is an ethoxylated TMPTA which is nearly similar in structure containing only longer (ethoxy) chains to the acryl group. The unsaturated acryl is assumed to be most important for the toxicological behaviour. Therefore based on this similarity it can be assumed that the toxicological behaviour is similar. TMPeoTA shows in few sensitisation tests sensitising capacity.

Based on all the integrated information there is the concern that TMPTA is a skin sensitizer and therefore this hazard is taken into account for risk assessment. This concern was also raised during the official classification.

Key study assignment:

Due to fact that an official classification as skin sensitizer was made by the NTP the studies used there were found to be suitable of reliability and relevance by the committee. As the decision of the committee is not published in detail and it is not traceable what ratings were made all studies here were integrated as weight of evidence trying to underline the decision of the NTP. No key study was assigned.

-Buehler test, guinea pig, Buehler protocol: not skin sensitising, 1 animal with effects (Cytec, Industrial Bio-Test, 1974, Brett B.)

-Ear swelling test, mice, NTP protocol: not skin sensitising ; no significant differences in the percentage of ear swelling  (NTP, Medical College Virgini, 2005)

-LLNA, Mice, radioactive, NTP protocol: not skin sensitising, no significant increase in lymph node cell proliferation (NTP, Medical College Virgini, 2005)

-GPMT, guinea pig Magnusson and Kligman protocol: skin sensitising, 4/10 (0.5%) and 10/20 (10.0%), (Publication: 1983, Nethercott et al.)

-GPMT, guinea pig, Magnusson and Kligman protocol: skin sensitising, 6/24 (challenge: 0.1%) and 16/24 (challenge: 0.5%), (Publication: 1984, Björkner, B.)

Human evidence skin sensitisation:

-Patch test of sensitised workers, Human, no protocol: skin sensitising, unequivocal positive reactions to 1% trimethylol propane triacrylate in petrolatum (Publication: 1977, Emmett E.A. et al)

-Patch test of sensitised workers, Human, no protocol: skin sensitising, 1/6 (0.1%) (Publication: 1983, Nethercott et al.)

-Patch test of sensitised subgroup, Human, no protocol: not skin sensitising, 0/243 (Publication: 1997, Kanerva et. al.)

Key value for chemical safety assessment

Skin sensitisation

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

Justification for selection of skin sensitisation endpoint:

There are valid study data available to assess the skin sensitising potential of TMPTA. Data constitute results from animal studies (LLNA, GPMT; Ear swelling test, Buehler) and human studies (patch tests). The study details are though sparse making identification of key studies difficult.

Due to fact that an official classification as skin sensitizer was made by the NTP the studies used there were found to be suitable of reliability and relevance by the committee. As the decision of the committee is not published in detail and it is not traceable what ratings were made all studies here were integrated as weigh of evidence trying to underline the decision of the NTP. No key study was assigned.

The overall data does not unambiguously point towards a sensitizing potential. Data do not point toward a strong sensitizing potential and thus the substance can be considered as a moderate sensitizer.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Skin sensitisation:

According to CLP substances shall be classified as skin sensitizer if there are positive results from appropriate animal test or human evidence. Based on the available results there is the concern that TMPTA has skin sensitising potential in humans and in some animals. Additionally the substance was officially classified by the NTP as sensitising.

In consequence the substance needs to be classified according to CLP (Regulation (EU) 1272/2008) as sensitising to skin.

Classification for sensitisation:

CLP: sensitising to skin (Skin. Sens 1)

 

Respiratory sensitisation:

No classification can be derived due to lack of information

 

Classification for respiratory sensitisation:

CLP: no additional labelling