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Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

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

The skin sensitization potential of TBEP has been assessed using a weight of evidence approach using two animal studies (a modified Buehler Test in guinea pigs and an LLNA in mice) as well as a human RIPT study, human exposure data and absence of structural alerts for skin sensitization.

Studies in Animals:

There are two unpublished reports of in vivo studies available for evaluation of this endpoint. Since the results of the studies are inconsistent, a weight of evidence approach has been used for assessment of this endpoint.

In a study similar to OECD Guideline 406, the modified Buehler test (Gabriel, 1980) (Rel 2) using 10 guinea pigs, 0.5 mL TBEP was administered as supplied to an intact skin site and occluded for 24 hours. Following removal of the test patch, the guinea pigs were left to rest for 24 hours. This procedure was repeated for the same test sites for a total of 10 applications. Following a 2 week rest period, a challenge application was made on fresh skin sites for 24 hours. Test sites were examined 24 hours after each induction application and at 24 and 48 hours after the challenge application. No signs of irritation (erythema or oedema) were reported at any stage. TBEP was assessed not to have any sensitizing potential in this study.

In a GLP study (Totok-Batho, 2010) (Rel. 1) following the OECD guideline 429 (Rel 1) for LLNA, TBEP was administered to the dorsal surface of the ears of femaleCBAmice (4 per group) at concentrations of 10, 25 and 50% in acetone/olive oil 4:1. The stimulation indices were 1.6 at 10%, 3.1 at 25% and 5.5 at 50%. TBEP was concluded to have sensitization potential in this study. The EC3value was approximately 24%, indicating TBEP to have moderate skin sensitization potential.

In order to determine whether the Buehler test or LLNA is more appropriate for risk assessment, a publication on strategies for identifying false positive results in predictive skin sensitization tests was reviewed (Basketter, 1998). The results of the LLNA were assessed for 14 substances with varying irritating potency. TBEP was not tested, but has been assessed against the criteria described in this publication.

Criteria listed as possible indicators that a positive result in LLNA may not be indicative of sensitization potential are: test substance does not have a structural alert, test substance is known to be a significant skin irritant, dose response is odd and/or weakly positive, only at high dose concentration, inter-animal and/or inter-experiment variation is high and draining lymph node cells do not have surface markers characteristic of skin sensitization. In the case of TBEP, at least three of these criteria are met: TBEP does not have a structural alert for skin sensitization potential, TBEP is a weak to moderate skin irritant (close to the classification / non-classification boundary for acute skin irritation) and inter-animal (guinea pig versus mouse) variation is high in the two available TBEP studies.

It can therefore be considered that the LLNA result (Torok-Batho, 2010) may not be indicative of sensitization potential for TBEP, but could be due to irritant properties.

Certain structural properties have been reported as being indicative of a chemical likely to have sensitization potential (Ashby et al, 1995). Five specific classes of agents were discerned: electrophiles, potential electrophiles after metabolism, Michael-reactive agents, benzoylating agents, and ionic chemicals in addition to some miscellaneous agents which could not be included in specific groupings. TBEP does not show any of the structural features predictive of sensitization potential.

Volunteer Studies in Humans:

TBEP was tested in a human repeated insult patch test (HRIPT) using the modified Shelanski procedure (Shelanski, 1984, Rel. 2). 209 volunteers (47 male and 162 female) were subjected to a three week induction period. Approximately 0.2ml of TBEP, as supplied, was placed on a webril pad of the bandage and the patch then applied to a designated site on the back. A series of 12 applications of 24-hour duration was conducted at the rate of 4 applications per week during the 3-week induction period. During the fourth week a series of four challenge applications on virgin sites was completed. All reactions were scored on a scale of 0 to 4. During the induction period minimal irritation (erythema) was observed on one occasion in 5 of the subjects and twice in 4 subjects. There was no dermal reaction to challenge. It was concluded that TBEP did not induce sensitization in this test procedure.

Human Experience:

TBEP has been manufactured, formulated into preparations and used in preparations at concentrations up to approximately 5% in professional applications over many years. No incidences of skin sensitization have been reported.

While negative data in human volunteer studies or workplace experience are not conclusive, they are supportive of the proposition that TBEP is not a skin sensitizer.

Conclusion:

Overall, the weight of evidence suggests that TBEP does not have significant skin sensitization potential. The available studies are considered sufficient to fulfill this endpoint.


Migrated from Short description of key information:
The skin sensitization potential of TBEP has been examined in a modified Buehler Test in guinea pigs (Gabriel, 1980, Rel. 2) and the LLNA in mice (Torok-Batho, 2010, Rel. 1). Neither can be considered as Key Study for this endpoint since the studies give conflicting results. Assessment for this endpoint has been made by weight of evidence, taking into account also a human RIPT study (Shelanski, 1984, Rel. 2), human exposure data and absence of structural alerts for skin sensitization.

Respiratory sensitisation

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

Respiratory Sensitization:

There have been no reports of respiratory sensitization from either the manufacture or the use of TBEP over many years of human experience. No experimental information is available or required for this endpoint.


Migrated from Short description of key information:
There are no data which indicate that TBEP has respiratory sensitization potential.

Justification for classification or non-classification

Skin sensitization:

Since the results of the two studies in animals by different protocols give conflicting results, it is appropriate to take all available information, including data from human experience, into account to assess whether classification for this endpoint is required.

Although a GLP-compliant study, using the LLNA in mice, concluded TBEP as having moderate skin sensitization potential, irritant potential may have been a confounding factor in this study, possibly leading to a “false-positive” result. A modified Buehler study in guinea pigs showed no evidence of sensitization potential. Data from human predictive tests (HRIPT) and practical experience have not revealed evidence of sensitization. Theweight of evidence from all the available sources therefore indicates that TBEP does not have significant potential for skin sensitization and does not require classification for this endpoint.

TBEP is therefore not classified for skin sensitization according to the criteria of Annex VI Directive 67/748/EECor UN/EU GHS.

Respiratory sensitization:

There are no data which indicate that TBEP has respiratory sensitization potential.

TBEP is therefore not classified for respiratory sensitization according to the criteria of Annex VI Directive 67/748/EECor UN/EU GHS.