Registration Dossier

Administrative data

Description of key information

Skin

The endpoint was addressed in Dreher D (2008), a GLP compliant study conducted to OECD 404. The mean scores for erythema and eschar formation and for oedema formation, for each rabbit, were zero.

The test article produced a primary irritation index of 0.0 and was classified as NON-IRRITANT to rabbit skin according to the Draize classification scheme. No corrosive effects were noted.

Further supporting information was provided in Menne et al. (1987), under Health surveillance data, who performed observations for skin irritation in human volunteers patch tested for tin induced reactions in Nickel sensitised individuals. The author concluded that pure tin metal was not a skin irritant.

Eye

Dreher D (2008) was provided as the key study to address eye irritation. The study was performed in compliance with GLP to the OECD guideline 405. Tin metal powder (2 -11 µm) was instilled, as 100 mg, into the lower conjunctival sac of three NZW rabbits. Ocular changes were assessed at 1, 4, 24, 48 and 72 hours post-exposure and fluorescein was applied after 24 hours.

Transient conjunctival redness and swelling occurred in two rabbits on day 1 and corneal opacity was briefly apparent for one animal on day 2/3. No iridial changes were noted. All reactions had overtly resolved by day 4 and the mean scores for each irritation parameter were below the threshold for classification.

Respiratory

Gaunt G (2009), presented as the key study under Acute toxicity: inhalation, included clinical observations post dosing. The study was performed in compliance with GLP and to a current standardised guideline for the testing of acute toxicity via the inhalatory route, the clinical observations were therefore considered to have been performed to a good scientific standard and considered adequate to base decisions on classification of the substance for respiratory irritation. No clinical signs were attributed to administration of the test material or indicative of respiratory irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 July 2008 to 25 July 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Three male rabbits obtained from commercial breeder, acclimated for 7-14 days. Hair removed from dorsum on day prior to treatment and animals confirmed to be healthy with intact, undamaged skin. Bodyweights recorded on day of arrival. Housed in standard laboratory cages - diet, water and environmental conditions complied with animal welfare and UK Home Office guidelines. Measures to enrich the environment using chew blocks and hay were included

TEST ANIMALS
- Source: Harlan UK Ltd., Bicester
- Age at study initiation: 12 to 15 weeks
- Weight at study initiation: 2.29 kg to 2.90 kg
- Housing: On arrival, rabbits were accommodated in cages that conform with the 'Code of Practice for the Housing and Care of Animals Used in Scientific Procedures' (Home Office, London, 1989).
- Diet: Global Diet TRB 2930C (Harlan Teklad, Bicester, UK), freely available to the animals at all times. Each batch of diet had been analysed for specific constituents and contaminants by the manufacturer.
- Water: Mains water was provided, ad libitum, via cage-mounted water bottles. The water had been periodically analysed for specific contaminants.
- Acclimation period: 7 to 21 days

ENVIRONMENTAL CONDITIONS
- Temperature: 15 to 21 °C
- Humidity: 40 to 70 %
- Air changes: 15 per hour
- Photoperiod: The rooms were illuminated by fluorescent strip-lights for twelve hours daily.

In order to enrich both the environment and the welfare of the animals they were, where practicable, provided with wooden Aspen chew blocks and hay.

Overtly healthy animals were arbitrarily allocated to the study on the day prior to dosing. Electric clippers were used to remove all hair from an area of the dorsum measuring approximately 10 x 8 cm. Only rabbits with dorsal skin showing no pre-existing damage, irritation or multiple areas of active hair growth were accepted onto study.
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg of tin metal powder (2-11 µm) per site

The test article was moistened with water before application in order to ensure good contact with the skin.

Duration of treatment / exposure:
4 hours under semi-occlusive dressing
Observation period:
72 hours
Number of animals:
Initially a single rabbit, followed by a further two animals.
Details on study design:
TEST SITE
- Area of exposure: 30 x 20 mm area on the closely clipped dorsum
- Type of wrap if used: The dose was spread uniformly over the designated area and then covered by a dense gauze patch (30 x 20 mm) on Day 1. This in turn was covered by a larger gauze patch (40 x 40 mm) and an open weave, elasticated adhesive compression bandage which was wrapped firmly around the torso to secure the applied dose and patch in the correct position. The dressing was considered to be semi-occlusive

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test patch was removed after four hours and the treated skin was lightly brushed clean of any solid residues and swabbed with moist cotton wool. The location of the test site was marked on the dorsum with indelible ink after completion of the cleansing process.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
Draize J H (1959) “Dermal Toxicity” in: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Association of Food and Drug Officials of the United States, Austin, Texas, p47 ( detailed under section "Any other information on materials and methods incl. tables")

Before the first animal could be dosed, the pH of the test article was checked. A 50 % w/v dispersion in purified water had a pH of 5. Since this was within the acceptable range of pH 2.0 to 11.5, the study continued.
Although no contemporary measurement of pH of the purified water used in the formulation was made, the water comes from one source and is produced on site at Covance, Harrogate from an Elgastat purifier. The typical pH value of the purified water is pH 5.68 (as measured on 03 October 2008)

Each rabbit was weighed on the day before dosing commenced (Day –1).
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 to 72 hour scores
Score:
0
Max. score:
0
Reversibility:
other: No reactions occurred at any time point for any any rabbit, so no possibility for reversibility
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No dermal response to treatment was observed in any animal throughout the observation period.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.

No dermal reactions were apparent at any site for any of the three rabbits, at any time point from 1 to 72 hours post-exposure.

Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
The mean scores for erythema and eschar formation and for oedema formation, for each rabbit, were zero. Therefore, the test article did not meet the criteria for classification as irritant or corrosive according to EU criteria.
The test article produced a primary irritation index of 0.0 and was classified as NON-IRRITANT to rabbit skin according to the Draize classification scheme. No corrosive effects were noted
Executive summary:

500 mg of tin metal powder (2 -11 µm) was applied to moistened sites on the clipped, shaved dorsum of three NZW rabbits and maintained in situ under a semi-occlusive dressing for 4 hours. The sites were assessed at 1, 24, 48 and 72 hours post-exposure and scored for signs of erythema or oedema according to Draize system. No dermal reactions were observed.

Tin metal powder (2 -11 µm) was not irritating and does not require classification as a skin irritant.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28 July 2008 to 15 August 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Principles of method if other than guideline:
Study conducted according to standard guideline
GLP compliance:
yes
Specific details on test material used for the study:
Particle size data is included in the attached image.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan UK Ltd, Bicester
- Age at study initiation: Approximately 12 to 15 weeks old
- Weight at study initiation: 2.63 to 2.87 kg
- Housing: On arrival, rabbits were accommodated in cages that conform with the 'Code of Practice for the Housing and Care of Animals Used in Scientific Procedures' (Home Office, London, 1989).
- Diet: Global Diet TRB 2930C (Harlan Teklad, Bicester, UK) available ad libitum. Each batch of diet had been analysed for specific constituents and contaminants by the manufacturer. (Global Diet 2030 was specified by the protocol, however the use of Global Diet TRB 2930C was not considered to affect the outcome or integrity of the study).
- Water: Mains water provided ad libitum provided via cage mounted water bottles. The water had been periodically analysed for specific contaminants.
- Acclimation period: 7 to 21 days

ENVIRONMENTAL CONDITIONS
- Temperature: 15 to 21 °C
- Humidity: 40 to 70 % (On three occasions the relative humidity exceeded the specified range with the highest value recorded being 74 %, this is not considered to have affected the integrity or outcome of the study).
- Air changes: 15 changes per hour
- Photoperiod: The rooms were illuminated by fluorescent strip lights for twelve hours daily.

IN-LIFE DATES: From 28 July 2008 to 15 August 2008

In order to enrich both the environment and the welfare of the animals they were, where practicable, provided with wooden Aspen chew blocks and hay.

The condition of the animals was assessed daily throughout the acclimatisation period of 7 to 21 days. A clinical inspection was performed prior to study commencement to ensure the animals were suitable for the test procedures. Overtly healthy animals were arbitrarily allocated to the study on the day before dosing. Both eyes of each rabbit were examined for indications of corneal, iridial or conjunctival damage or irritation. After initial visual examination, one drop of 1 % aqueous fluorescein solution was instilled into both lower conjunctival sacs, allowed to disperse for thirty seconds and removed from the eyes by irrigation with approximately 10 mL water for irrigation jetted gently from a syringe. The corneal surface was illuminated with an ultraviolet source and inspected for areas of absorption of the fluorescing dye that would indicate epithelial damage. Only rabbits with eyes free from damage or irritation were accepted onto study.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg

One dose consisting of 100 mg of test article was instilled into the left conjunctival sac of a single New Zealand White rabbit (the sentinel). The lower eyelid was gently prised away from the eyeball to create a receptacle for the dose. After instillation, the eyelids were held closed for a few seconds to prevent loss of the dose. The right eye remained untreated and served as a control to the treated eye.
Duration of treatment / exposure:
Exposure was indefinite since no immediate rinsing occurred.
Observation period (in vivo):
Animals were assessed for the initial sting/pain response immediately after instillation of the test material. Ocualr assessments were performed at 1, 4 and approximately 24, 48 and 72 hours after instillation
Number of animals or in vitro replicates:
One animal initially, followed by a further two animals.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Exposure was indefinite since no immediate rinsing occurred. The treated eyes were subject to fluorescein application and subsequent flushing with water at 24 hours post-instillation and this can be taken to have flushed away any residual test material.

SCORING SYSTEM: At examinations carried out 24 hours after treatemtn (and at the discretion of the observer, at any subsequent examination) the cornea was subject to application of 1 % aqueous fluorescein solution followed by irrigation with water and illumination by an ultraviolet sourve. Damage to the corneal epitheliam was revealed by absorption of the fluorescing dye into the epithelium or stroma. The scoring systems for initial pain response and ocular changes are reported below under section "Any other information on material and methods incl. tables)

TOOL USED TO ASSESS SCORE: pencil-beam torch

The pH of a 50 % dilution of tin metal powder in water was checked prior to exposure of the first eye. The test material was suspended in water at a 50 % w/v dispersion. The pH of the test material was determined to be 5 which is within the acceptable range.
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Slight conjunctival redness apparent in one treated eye at 24 and 48 hours had resolved by the day 4 assessment
Irritant / corrosive response data:
Instillation of the test article caused no initial sting response.
Minimal conjunctival irritation was noted in two treated eyes 30 minutes and one hour after instillation.
No iridial effects were seen.
No corneal opacity was noted in two treated eyes. There was no corneal absorption of fluorescein solution when applied to these eyes at the 24-hour observation.
Easily discernible areas of corneal opacity were noted in one treated eye on Day 2, with scattered or diffuse areas of opacity noted on Day 3. The application of fluorescein solution at these time points gave fluorescence over an area of < 25 % of the corneal surface.
The eyes of all rabbits were overtly normal by the 72-hour examination.
Other effects:
No observations indicative of systemic toxicity or ill health were noted for any rabbits during the course of the study.

Table 1: Individual and mean scores for cornea, iris and conjunctivae for classification according to Commission Directive 2001/59/EC

Rabbit Number and Sex

Observation Time

Corneal Opacity

Iridial Inflammation

Conjunctival Redness

Conjunctival Chemosis

32 M

24 Hours

0

0

0

0

48 Hours

0

0

0

0

72 Hours

0

0

0

0

Total

0

0

0

0

Mean Score

0.0

0.0

0.0

0.0

33 M

24 Hours

0

0

0

0

48 Hours

0

0

0

0

72 Hours

0

0

0

0

Total

0

0

0

0

Mean Score

0.0

0.0

0.0

0.0

34 M

24 Hours

2

0

0

0

48 Hours

1

0

0

0

72 Hours

0

0

0

0

Total

3

0

0

0

Mean Score

1.0

0.0

0.0

0.0

 

Table 2: Individual ocular responses

Rabbit number and sex

Initial sting response

Observation

Score at time after instillation

½ hr

1 hr

4 hrs

24 hrs

48 hrs

72 hrs

32M

 

 

0

Cornea

Opacity

0#

0#

0#

0*

0

0

Area

0

0

0

0

0

0

Iris

 

0

0

0

0

0

0

 

Conjunctivae

Redness

0

0

0

0

0

0

Chemosis

0

0

0

0

0

0

Discharge

0

0

0

0

0

0

33M

 

 

 

Cornea

Opacity

0#

0#

0

0*

0

0

Area

0

0

0

0

0

0

Iris

 

0

0

0

0

0

0

 

Conjunctivae

Redness

1

1

0

0

0

0

Chemosis

1

1

0

0

0

0

Discharge

0

0

0

0

0

0

34M

 

 

0

Cornea

Opacity

0#

0#

0

2*

1*

0

Area

0

0

0

1

1

0

Iris

 

0

0

0

0

0

0

 

Conjunctivae

Redness

1

1

0

0

0

0

Chemosis

0

0

0

0

0

0

Discharge

0

0

0

0

0

0

* Fluorescein applied to cornea

# Small amount of test article visible on both eyelids

Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
Tin metal powder instilled as 100 mg into three rabbit eyes did not elicit any significant irritant reactions. Ocular changes (slight conjunctival and corneal responses) had resolved by day 4. No classification as an ocular irritant is appropriate.
Executive summary:

Tin metal powder (2 -11 µm) was instilled, as 100 mg, into the lower conjunctival sac of three NZW rabbits. Ocular changes were assessed at 1, 4, 24, 48 and 72 hours post-exposure and fluorescein was applied after 24 hours.

Transient conjunctival redness and swelling occurred in two rabbits on day 1 and corneal opacity was briefly apparent for one animal on day 2/3. No iridial changes were noted. All reactions had overtly resolved by day 4 and the mean scores for each irritation parameter were below the threshold for classification.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin

Dreher D (2008) was submitted as the key study to fulfil this endpoint. The study was performed in compliance with GLP and to a current standardised guideline. Accordingly the study was assigned a reliability score of 1 in line with the criteria outlined in Klimischet al. (1997), and considered adequate and reliable for classification.

Supporting information was available in the form of Menne (1987), detailed under Health surveillance data. The study was performed to a good scientific standard, however the observations concerning skin irritation in subjects was a brief observation included in the discussion of the paper.

 

Eye

The key, standalone study, Dreher D (2008) was considered adequate and reliable for classification of the substance. The study was performed in line with current standardised guidelines and in compliance with GLP, accordingly the substance was assigned a reliability score of 1 in line with the criteria outlined in Klimisch et al. (1997).

Respiratory

The observations of Gaunt G (2009) were assessed for the purpose of classification for irritation of the respiratory tract. The study was performed in compliance with GLP and to a current standardised guideline for testing acute toxicity via inhalation (OECD 403). The observations were considered to have been performed to a good scientific standard and therefore assessed for classification and labelling purposes. Furthermore, studies such as Robertson (1960) which include monitoring during manufacture of pure tin do not report respiratory tract irritation of tin, or tin oxide which is linked with stannosis.

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, eye or respiratory irritation. No reactions were noted in the experimental data presented, or from data in the public domain concerning exposure to humans.