Registration Dossier

Administrative data

Description of key information

Skin

In accordance with Annex XI of the regulation EC No. 1907/2006, point 1.1.3. testing may be omitted if assessment of historical human data provides sufficient information for classification and labelling purposes. An expert review detailing available data and experiences of experts in the field of dermatology and skin sensitisation was provided in support of omitting unecessary testing.

Respiratory

Documented human exposure presented under health surveillance data  showed no evidence of respiratory sensitisation resulting from exposure to tin or tin compounds, even under working conditions with poor risk management measures and high levels of exposure.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation, other
Remarks:
other: Various - see attached background information
Type of information:
other: Review
Adequacy of study:
supporting study
Study period:
not reported.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
An extensive expert report written by a leading expert in the field of sensitisation assessing the available data in the public domain concerning the potential of metallic tin to act as a sensitiser.
Principles of method if other than guideline:
A variety of investigational techniques and approaches were used to determine potential sensitising capabilities of metallic tin. These are outlined in the attached background information and summarised in the overall review .
GLP compliance:
no
Type of study:
other: Various - see attached background information
Species:
other: human, guinea pig, rat and mouse data reviewed
Strain:
other: Sensitisation discussed in a variety of species and strains
Sex:
male/female
Route:
other: Various routes of challenge, often not determinable in the human subjects discussed in the various available studies.
Vehicle:
other:
Remarks:
various methods of administration employed in the reviewed studies.
Concentration / amount:
Variable depending of the route of administration
Route:
other: various routes of challenge
Vehicle:
other: various methods of administration employed in the reviewed studies.
Concentration / amount:
Variable depending of the route of administration
No. of animals per dose:
There was a large variety in the study size depending on the type of study reviewed in the expert report
Details on study design:
Review of clinical experience, historical data for animal studies

Based on the available data presented in literature, and studies and testimonies from interviews with dermatologists a strong argument was presented that tin was not a skin sensitiser. Furthermore despite widespread historical of use tin and being freely available to the public, there is no evidence of skin sensitisation in recorded history.

Interpretation of results:
other: Not classified in accordance with EU criteria according to expert judgement
Conclusions:
The review of available information relating to sensitisation and human contact dermatitis, discussed withtin the expert review, concluded that no classification of metallic tin as a sensitiser is warranted.
Executive summary:

An extensive expert report is available written by a leading expert in the field of sensitisation assessing the available data in the public domain concerning the potential of metallic tin to act as a sensitiser.

Firstly, a salutary reminder: the tin can was invented almost 200 years ago, its success arising in no small part from the resistance of tin to corrosion, dissolution, reaction etc.  From first principles, these properties suggest metallic tin is not likely to represent a significant skin sensitisation hazard.  Indeed, to act as a skin sensitiser, a substance must possess two key properties, the ability to penetrate to a sufficient extent into the viable epidermis (recently reviewed in Basketter et al., 2007) and, once there, to bind firmly with skin proteins (recently reviewed in Divkovic et al., 2005).  It is considered that metallic tin is not readily able to achieve either of these.  Nevertheless, it must be remembered that skin sensitisation can be driven by relatively modest amounts of a substance, so the other data must be considered.

Concerning chemistry, structure activity relationships and so forth, then this is always a problematic territory.  However, tin is clearly not a highly reactive metal and does not reside in the periodic table in close association with known metal skin sensitisers, e.g. Ni, Cr, Co, Au, and it is judged that this therefore should give some degree of confidence that it is unlikely to behave as a skin sensitiser.  Clearly, an expert in the chemistry of metals and their interaction with organic materials such as proteins may be able to clarify this matter further. As far as the review report can ascertain, there is no animal skin sensitisation study of metallic tin.  This is not surprising; many metals have been tested as one or other of their salts, quite often the chloride, as this is the salt normally produced on the skin by interaction with (corrosive) sweat.  The resistance of tin to corrosion means that generation of tin chloride on the skin is considered to be less likely.  It is therefore relevant to note that neither of the tin chloride salts has been evaluated in predictive skin sensitisation assays, and only the divalent salt having been used in diagnostic patch testing (TNO Report, 2007). 

Next, what does the clinical data on tin convey concerning skin sensitisation hazard?  There is initial observational data which is suggestive of some potential, but this has not translated into any significant further evidence some two decades later, either published or in the awareness of leading figures of as yet unpublished information.  Does this represent a quantity of human evidence sufficient to trigger classification according to regulatory criteria?  It is considered that it does not.  The reports represent no more than isolated reports, very largely from a single clinic.  If all of these cases actually were true contact allergy (their clinical relevance was not established, so to refer to them as allergic contact dermatitis is incorrect), then they are not greater in number than the isolated cases of petrolatum allergy that have been reported (Schnuch et al., 2006).  There is of course no question that petrolatum could ever be regarded as anything other than a non-sensitising substance. 

To finish, it is noted that the REACH Regulation, as others before it, requires (a sufficient body of) human evidence of allergic contact dermatitis to trigger classification.  For metallic tin, not only is it no more frequent a contact allergen than petrolatum, in contrast to the latter, it has never been shown to have any relevance and therefore has never been reported as a cause of allergic contact dermatitis. Of course, an absence of clinical evidence means little if there has not been, over a period of years, a fair degree of exposure to tin.  Although data on exposure was not available to the report author, the complete absence of occupational skin disease in industries producing/using tin and the total absence of any consumer problems seems to be significant when one bears in mind that diagnostic patch testing began in the late 19th century and became common practice more than 50 years ago (Lachapelle, 2006).  In this context, the positive patch test results with tin II chloride should be mentioned.  Both the clinical significance of this data and its relevance to metallic tin is unknown.  However, since there are no sequelae to the work, and it seems quite probable that skin irritation played a significant part in the skin responses seen, then it is judged the data does not generate any material concern regarding skin sensitisation and metallic tin.

Lastly, does the other immunotoxicology data give any cause for concern regarding potential skin sensitisation hazard?  It is concluded that it does not.  Indeed, it could be argued that it positively suggests metallic tin is unlikely to be a skin sensitiser.  Plasma cells are not responsible for skin sensitisation (see the recent mechanistic review by Rustemeyer et al., 2006).  To add strength to this, it is considered important to note that the classic human metal skin sensitisers, nickel and chromium, both fail to produce responses of the kind generated by tin in certain rat strains.  If classic and common human allergens do not produce this response, it argues most powerfully that it is not an indication that metallic tin is a potential skin sensitiser.

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

Basketter D (2008) was provided to address tin as a skin sensitiser. Within the report, physicochemical and toxicological data was assessed to present an overall picture of the sensitising potential of tin. The author, a leading expert in the field of sensitisation, also consulted with dermatologists and drew upon their experiences, as well as his own to provide a comprehensive review of the sensitising potential of tin. As such the data presented was considered reliable and adequate to assess the registered substance based on the conclusions of the report. Furthermore, as tin is not traditionally known as a sensitiser despite its extensive use throughout history, this further confirms the conclusions drawn.

Respiratory sensitisation

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

The Health surveillance study, Robertson (1960), despite mainly focussing on workers exposure to tin oxide, also considered workers exposed to pure tin metal in a smelting works. No incidence of respiratory sensitisation was reported.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to skin or respiratory sensitisation as there is no historical evidence of skin or respiratory sensitisation despite extensive historical use.