Tin

Endpoint summary

Description of key information

Oral

In the GLP compliant key study (Dreher, 2009) performed to the current standardised guideline OECD 423, the acute median lethal oral dose level of the test article, Elemental Tin Powder (2 – 11 µm), was found to exceed 2000 mg/kg.

This is confirmed by the results of the supporting study (Parcell, 1994), also performed in compliance with GLP and to the OECD guideline 423 in which the test material was found to be of low acute oral toxicity (LD50 >2000 mg/kg bw).

Inhalation

Gaunt, 2008, was provided as the key study for this endpoint. The study was performed in compliance with GLP and to the OECD guideline 403. The maximum practically achievable, respirable concentration of tin metal powder in the study was 4.75 mg/L. In the absence of adverse clinical signs or pathology findings it is considered that the LC50 is in excess of 5 mg/L.

Dermal

Bradshaw, 2009 was provided as the key study for this data requirement. The study was performed in compliance with GLP and to the standardised guideline OECD 402. Under the conditions of the study, the acute median lethal dermal dose of tin to Wistar rats was greater than 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

22 December 2008 to 13 January 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl:CD (SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd, Margate
- Age at study initiation: 8-9 weeks old
- Weight at study initiation: 180-225 g
- Fasting period before study: yes overnight
- Housing:The animals were housed in groups of up to five during the acclimatisation period. From the day prior to dosing (Day-1), the rats were housed in groups of three in similar cages. The animals were provided on a weekly basis clean Aspen wood chips (Datesand Ltd, Manchester UK) as bedding. The bedding had been analysed for specific contaminants and the results retained on file at Covance.
- Diet (e.g. ad libitum): SQC(E) Rat and Mouse Maintenance Diet No 1, from Special Diets Services Ltd, Witham UK was available ad libitum except for a period of fasting from the evening of the day prior to dosing. Each batch of diet had been analysed for specific constituents and contaminants by the manufacturer.
- Water (e.g. ad libitum): Mains water in cage mounted water bottles, available ad libitum. The water had been periodically analysed for specific contaminatns.
- Acclimation period: 7-14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 40-70 % RH
- Air changes: 15 air changes per hour
- Photoperiod: The rooms were illuminated by fluorescent strip-lights for twelve hours daily.

IN-LIFE DATES: From: 22 December 2008 To: 13 January 2009

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: 1 % aqueous carboxymethylcellulose (sodium salt) was found to be an appropriate suspending agent giving a homogeneous stable formulation

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Information from acute toxicity investigations suggested tin was not toxic at the regulatory limit dose

Doses:

Two groups of three females dosed at 2000 mg/kg bw

No. of animals per sex per dose:

Three females

Control animals:

no

Details on study design:

- Duration of observation period following administration: Animals were sacrificed on day 15.
- Frequency of observations and weighing: Treated rats were observed for clinical sign of reaction to treatment. Clinical signs were recorded immediately post-dose at approximately 15 and 30 minutes post-dose, hourly between 1 and 4 hours post-dose (inclusive), twice daily on Days 2, 3, and 4 and once daily from the fifth to last day of the observation period. The second observation was not conducted on day 4 for the first group of animals. Rats were weighed on Day-1 (day before dosing) and on Days 1, 4, 8 and 15.
- Necropsy of survivors performed: Yes. Rats were killed on Day 15. Each animal was given an intraperitoneal injection of sodium pentobarbitone. Once a suitably deep plane of anaesthesia had been established, the animal was exsanguinated by the severing of major blood vessels. After exsanguination a full macroscopic necrospy was performed and all lesions were recorded.
The necropsy procedure included inspection of external surfaces and orifices, all viscera and tissue within the abdominal, thoracic and cranial cavities, free-hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach, small and large intestines. No tissue preservation or histopathological assessment of tissues was undertaken.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortalities

Clinical signs:

other: No clinical signs of reaction to treatment observed

Gross pathology:

No macroscopic abnormalities were observed

Other findings:

No indications of systemic toxicity following oral administration of the limit dose, 2000 mg/kg bw, of metallic tin powder rendered highly absorbale by grinding to produce a standardised powder with granules in the range of 2-11 µm.

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

The acute median lethal oral dose level of the test article, Elemental Tin Powder (2 – 11 µm), was found to exceed 2000 mg/kg.

Executive summary:

Oral administration of a suspension of Tin powder (2 -11 µm) in aqueous CMC was administered to two groups of three female rats at the limit dose level according to the Acute Toxic Class guideline, OECD 423 (performed in compliance with GLP). The treated rats were observed for mortality and clinical signs over a 14 day observation period. Bodyweights were recorded prior to, and on, the day of dosing and on days 4, 8 and 15. Necropsy was completed on day 15.

There were no mortalities, no signs of reaction to treatment, no effects on bodyweight and no abnormalities observed during necropsy.

The acute median lethal oral dose level of the test article, Elemental Tin Powder (2 – 11 µm), was found to exceed 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The overall quality of the database is high. The key study was conducted under GLP conditions and in accordance with standardised guidelines.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 September 2008 to 8 October 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The information obtained is relevant to to hazard assessment of metallic tin and all efforts were made to determine as accurately as feasiblly possible, the likely inhalation or respiratory effects of exposure to tin metal.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Limited, Margate, Kent UK
- Age at study initiation: 57 days (males) and 78 days (females)
- Weight at study initiation: 230-251g (males) and 199-221g (females)
- Fasting period before study: no
- Housing: in groups of five in standard laboratory caging
- Diet: ad libitum, SQC Rat and Mouse Maintenance Diet No 1, Expanded, (Special Diets Services Ltd, Witham, UK)
- Water: ad libitum, mains water via water bottles
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 40-70% RH
- Air changes: 15 per hr
- Photoperiod:12/12 (hrs dark / hrs light)

IN-LIFE DATES: From: 17 September 2008 To: 1 October 2008

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

not specified

Mass median aerodynamic diameter (MMAD):

3.34 µm

Geometric standard deviation (GSD):

2.38

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Rotating brush generator and flow through chamber
- Exposure chamber volume: 40 L
- Method of holding animals in test chamber: Standard holding tubes (polycarbonate type restraining tubes) attached to chamber walls to give nose-only exposure
- Source and rate of air: Generator, 20.1 L/min flow rate to achieve 12 air changes per hour
- System of generating particulates/aerosols: Rotating brush generator
- Method of particle size determination: Supplied test material was ground to produce a powder with particle size of 1-5 µm. Samples were returned for analysis and confirmation of particle size range. Particle sizes in the test aerosol were measured gravimetrically using a Marple 298 cascade impactor, from which the MMAD and GSD were determined. During the aerosol characterisation phase of the study, samples of the generated tin metal powder were sent to the Sponsor for examination under a microscope to check that agglomeration of the particles had not occurred during generation. The tin metal particles were collected from a port representative of the animals breathing zone. The duration of collection was 5 minutes. The tin particles were collected on Vaseline smeared glass slides. The slides were not directly analysed by scanning electron microscope (SEM) as it was expected that the Vaseline would degas in the SEM machine. Carbon tape was pressed onto the glass slide and then lifted off to collect a sample of tin powder and was then gold coated before being viewed by SEM.
- Treatment of exhaust air: The chamber was exhausted from the bottom of the chamber to ensure a dynamic flow of fresh aerosol through the chamber during exposure. Treatment of exhaust air was not reported.
- Temperature, humidity, pressure in air chamber: Measured continuously within the chamber along with oxygen content with targets of 20-24 °C; 30-70 % RH and 19 % v/v oxygen.

TEST ATMOSPHERE
- Brief description of analytical method used: Nominal test atmosphere concentration determined and achieved concentration determined by gravimetric analysis at half hourly intervals throughout the exposure period
- Samples taken from breathing zone: yes

VEHICLE
No vehicle employed

TEST ATMOSPHERE (if not tabulated)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.34 µm and 2.38 respectively

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

>= 4 h

Concentrations:

4.75 mg/L measured (5 mg/L target)

No. of animals per sex per dose:

Five males and five females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Hourly observations during exposure and at daily intervals from day 2 to 15. Bodyweights recorded on daily.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology.

At necropsy the respiratory tract tissues were preserved for histopathology. The tissues included trachea, lung including main stem bronchi and bronchioles, tracheal bifurcation (bronchial), larynx, and nasopharynx.

Histopathological examinations included trachea, mainstem bronchi, bronchioles and lung for two animals per group

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4.75 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortalities during the study

Clinical signs:

other: Treatment-related clinical signs observed on Day 1, during exposure to 4.75 mg/L tin metal powder were limited to tachypnoea (abnormally fast breathing). This observation was seen in all animals (both sexes) from 3 hours onwards during exposure. Wet fur w

Body weight:

All animals lost weight during exposure. The mean post exposure body weight loss (14 g) was considered to be due to removal of food and water during the exposure period and not due to the effects of the test article. This weight loss is considered to be a common phenomenon observed in acute inhalation studies. All animals gained weight on Day 2, however, females took longer on average to recover their pre-exposure body weight.

Gross pathology:

Dark lung was noted in all animals at necropsy. This observation is consistent with inhalation exposure to respirable particulate material. There were no other macroscopic findings due to effects of the test article. Most tissues were macroscopically unremarkable and the findings seen were generally consistent with the usual pattern of findings in animals of this strain and age.

Other findings:

- Histopathology:Microscopic evaluation of the trachea, mainstem bronchi, bronchioles and lung was performed on two animals of each sex. In addition, representative photomicrographs of intra-alveolar particles in the lung, and intra epithelial particles in the trachea were taken using a digital camera attached to a microscope.
Test article was noted in the lung in all treated animals examined which generally correlated with findings seen macroscopically of heavy staining in the lungs. In one male, sub-epithelial particles were noted in the trachea.
Test article in the lung was characterised by multiple dark particles in the alveolar spaces, generally associated with pale eosinophilic homogenous material, and occasionally within alveolar macrophages. Particles were located in all lung sections and distributed from alveoli in the deep lung parenchyma to sub-pleural alveoli, with no clear anatomic localisation. In addition, there were occasional very minor foci of mucus-associated particles adherent to the bronchial and/or bronchiolar epithelium.
Sub-epithelial particles in the trachea were characterised by a few dark particles associated with minor lymphoid foci localised beneath the epithelium of the carina of the tracheal bifurcation.
There were no other microscopic findings due to effects of the test article.

Table1

Group summary clinical signs

Group/Sex		Clinical sign	Number of animals in group showing signs during exposure on Day 1 (hours):		Number of animals in group showing signs post-exposure on Day 1 (hours):
			3	4	Imm	1	2	3	4
1M		Number examined:	5	5	5	5	5	5	5
		Tachypnoea	5	5
		Wet fur	5	5	5
		Unkempt				5	5	5	5
		Staining - head			5
		Staining*				3	2	1	2
		Vocalisation			1
1F		Number examined:	5	5	5	5	5	5	5
		Tachypnoea	5	5
		Wet fur	5	5	5
		Unkempt				5	5	5	5
		Staining - head			5
		Staining*				5	3	2	1
		Vocalisation			3

Imm = Immediately on return to cage
* where no area has been specified, this indicates that staining was seen across the whole of the animal's body

Table2
Group mean body weights

Group/ Sex	Animal number	Group mean body weights (g) for Day:
		1 (Pre-exposure)	1 Post-exposure	2	3	4	5
1M	Mean	239	225	239	245	246	249
	SD	8.5	7.3	9.7	9.4	8.8	11.5
1F	Mean	211    9.8	197	210	210	209	211
	SD		8.2	9.5	11.5	9.6	10.4

 

Group/ Sex	Animal number	Group mean body weights (g) for Day:
		6	7	8	9	10	11
1M	Mean	256	258	260	263	266	268
	SD	8.5	9.5	8.9	9.6	10.8	11.5
1F	Mean	213	213	214	214	216	216
	SD	9.8	10.4	9.0	9.1	10.2	13.3

 

Group/ Sex	Animal number	Group mean body weights (g) for Day:
		12	13	14	15
1M	Mean	271	274	279	279
	SD	12.6	11.8	12.8	12.6
1F	Mean	213	215	217	220
	SD	10.7	11.5	12.4	12.7

 

Table3
Group mean body weightgains

Group/ Sex	Animal         number			Pre-exposure body weight (g)	Body weight gain relative to pre-exposure(g)
					Day 1 post-exposure		Day 2	Day 8	Day 15
1M	Mean			239		-14	0	21	40
	SD			8.5		3.6	1.7	5.4	8.4
1F	Mean			211		-14	-1	3	9
	SD			9.8		3.9	3.4	7.4	5.5

 

Table 4
Particle Size

	% Mass of total
Cut point (µm)	100	21.3	14.8	9.8	6.0	3.5	1.55	0.93	0.52	MMAD (µm)		GSD
Stage	1	2	3	4	5	6	7	8	Filter
Gravimetric
PSD 1	100	100	100	98.43	35.08	19.37	14.14	11.52	5.76		3.82	2.76
PSD 2	100	99.32	99.32	99.32	40.54	20.27	12.16	9.46	6.08		3.06	2.21
PSD 3	100	100	99.29	99.29	43.26	19.86	12.77	7.80	4.26		3.15	2.17
Mean											3.34	2.38

MMAD = Mass median aerodynamic diameter

GSD = Geometric standard deviation

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

All animals survived a single 4-hour (nose only) inhalation exposure to tin metal powder. The mean achieved aerosol concentration during the 4 hour exposure was slightly below the OECD target dose level however, this concentration is considered to be the maximum practical achievable in order to maintain a respirable aerosol.
The mass median aerodynamic diameter (MMAD) was below 4 microns and therefore the particle size distribution was within the respirable range for rats.
No treatment related adverse effects were noted during the study. Macroscopic findings were consistent with exposure to dark material within the respirable range. Microscopic evaluation demonstrated that the test article had penetrated the deep lung.
The maximum practically achievable, respirable concentration of tin metal powder was 4.75 mg/L. In the absence of adverse clinical signs or pathology findings it is considered that the LC50 is in excess of 5 mg/L. The European Union (EU) classification of inhalation risk for test articles with an LC50 of greater than 5 mg/L is ‘unclassified’.

Executive summary:

A group of male and female rats was dosed with the maximum practical dose concentration of particulate tin metal, prepared as a dust in size range of 1 -5 µm. Nose only exposure for 4 hours was followed by 14 days observation, macroscopic and microscopic investigations were completed after necropsy. The LC50 for metallic tin dust was greater than 4.75 mg/L. No signs of a toxic response were evident following inhalation exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

5 000 mg/m³ air

Quality of whole database:

The overall quality of the database is high. The study was conducted under GLP conditions and in accordance with standardised guidelines.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 September 2009 to 14 October 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Principles of method if other than guideline:

Standard method - a group of five male and five female rats were exposed topically for 24 hours to a dose of 2000 mg/kg bw applied under a semi-occlusive dressing to intact dorsal skin. Clinical signs and bodyweight progression were monitored over the following two weeks and a full macroscopic examination completed at termination

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK BIcester, Oxon, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: at least 200 g (males - 225 to 247 g; females - 202 to 227 g on day 0)
- Fasting period before study: not applicable
- Housing: suspended polypropylene caging. Individually housed during treatment and group housed up to 5 rats per sex after dressing removal
- Diet: Available ad libitum. 2014 Teklan Global Rodent diet supplied by Harlan Teklad, Blackthorn Bicester, Oxon, UK.
- Water: Available ad libitum. Mains drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 30-70 % RH
- Air changes: 15 per hr
- Photoperiod: 12/12 (hrs dark / hrs light)

IN-LIFE DATES: From: 30 September 2009 To: 14 October 2009

Type of coverage:

semiocclusive

Vehicle:

arachis oil

Details on dermal exposure:

TEST SITE
- Area of exposure: 8 x 10 cm area on the dorsum
- % coverage: 10 %
- Type of wrap if used: surgical gauze and adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): cotton wool moistened with arachis oil
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw adjusted for individual rat bodyweight on Day 0
- Concentration (if solution): not applicable
- Constant volume or concentration used: no
- For solids, paste formed: yes - powder moistened with arachis oil BP

VEHICLE
- Amount(s) applied (volume or weight with unit): Sufficient to moisten individual doses
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not specified
- Purity: not specified (arachis oil BP)

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing, and subsequently once daily for fourteen days.
- Frequency of observations and weighing:daily observations. Bodyweights recorded at day 0, 7 and 14. After the removal of the dressings and subsequently once daily the test sites were examined for evidence of primary irritation.
- Necropsy of survivors performed: At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominaal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Statistics:

Data evaluations included the relationship, if any, between the exposure of the animal to the test material and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects.
Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test amterial was made.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There were no deaths.

Clinical signs:

other: No clinical signs indicative of reaction to treatment or of systemic toxicity were observed

Gross pathology:

No macroscopic abnormalities were evident during necropsy.

Other findings:

There were no dermal reactions at the treated sites.

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

The acute median lethal dermal dose to Wistar rats was greater than 2000 mg/kg bw.

Executive summary:

A group of five male and five female Wistar rats was topically treated with 2000 mg/kg bw of tin metal powder (prepared to provide a particle size in the range 2 -11 µm) in a GLP compliant study conducted to current internationally accepted guidelines (OECD 402 and EU Method B.3). No evidence was found for dermal toxicity at the limit dose level.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The overall quality of the database is high. The study was conducted under GLP conditions and in accordance with standardised guidelines.

Additional information

Oral

Dreher 2009 was selected as the key study for assessment as it was performed in compliance with GLP and to the OECD guideline 423. The study was accordingly assigned a reliabiltiy score of 1 and considered adequate for classification and labelling purposes. Parcell 1994 was provided as supporting information, the study was performed in compliance with GLP and to a standardised guideline, however no details were given on the particle size of the tin powder administered. The study was assigned a reliability score of 1 in accordance with the criteria of Klimisch et al. (1997).

Inhalation

Gaunt 2008 was provided as the key study to address acute toxicity via the inhalatory route. The study was performed in compliance with GLP and to a current standardised guideline. As such the study was assigned a reliability score of 1 and considered suitable for classification and labelling purposes.

Dermal

Bradshaw 2009 was considered adequate for classification and labelling purposes, and was submitted as the key study. The study was assigned a reliability score of 1 in line with the criteria of Klimisch et al. (1997) as the study was performed in compliance with GLP and to the current OECD guideline 402.

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 acute toxicity, as dosing at the limit for each of the three routes of exposure failed to induce any effects.