Tin

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

9 January 2009 to 9 March 2009; analyses completed on 03 September 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

The purpose of the study was to characterise the routes and rates of excretion of tin in urine and faeces following a single oral administration of elemental tin, using ICP-MS and ICP-AES techniques.

GLP compliance:

yes

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Sprague-Dawley Crl: SD (CD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd, Margate, Kent
- Weight at study initiation: 190-213 g males and 181 to 202 g females
- Housing: Group housed - up to 5 rats per sex in solid floor polycarbonate cages prior to dosing/collection of excreta
- Individual metabolism cages: yes for duration of excreta collection post-dosing in all glass metabolism cages.
- Diet: ad libitum, commercial pelletd diet SQC Rat and Mouse Maintenance Diet No 1, Expanded (Special Diets Services)
- Water: ad libitum, mains drinking water supplied by cage bottles.
- Acclimation period: 7 days

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

IN-LIFE DATES: From: 09 January 2009 To: 9 March 2009.

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Elemental tin was formulated as a fine suspension in 1 % (w/v) carboxymethyl cellulose (sodium salt) to a final volume of 25.3 mL at the required concentration (nominally 200 mg/mL). The formulation was mixed on a magnetic stirrer for about 20 minutes and then left to stand. It was then mixed on a magnetic stirrer immediately before and during the dosing procedure in order to ensure homogeneity.

A single daily preparation on the first day of dosing

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 25.3 mL final volume -, administered at dose volume of 10 mL/kg bw

HOMOGENEITY AND STABILITY OF TEST MATERIAL: maintained by continuous stirring

Duration and frequency of treatment / exposure:

Single oral administration on day 1

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose / concentration:

Three males and three females treated and one of each sex given vehicle alone as a concurrent control

Control animals:

yes, concurrent vehicle

Details on study design:

No further information

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, cage washes, diet, water and residual carcass
- Time and frequency of sampling: Urine and faeces were collected over approximately 24 hours prior to dosing and at the following intervals after dose administration: 0-8, 8-24, 24-48, 48-72, 72-96, 96-120, 120-144 and 144-168 hours
- Method type(s) for identification: ICP-MS for urine samples and ICP-AES for all other analyses.
- Limits of detection and quantification:
ICP-MS: The lower limit of quantification (LLOQ) was defined as the lowest non-zero standard concentration (0.02 ng/mL) providing it meets the acceptance criteria; sample results falling below the LLOQ are reported as ICP-AES: The lower limit of quantification (LLOQ) was defined as the lowest non-zero standard concentration (0.05 μg/mL); sample results falling below the LLOQ are reported as

Statistics:

Tin content in the urine samples was calculated as follows:
Urine tin content (μg/g) = instrument result (ng/mL) x 50/weight of urine sub sample (g)
Urine tin content (μg) = Urine tin content (μg/g) x total urine weight (g)
Tin content in the faeces/carcass/cage wash/cage debris samples was calculated as follows:
Tin content (mg) = (instrument result (μg/mL)/2 (Assuming sample did not require further dilution after the preparation stage (final volume equivalent to 500 mL))

Type:

excretion

Results:

96.9 and 99.7 % in the faeces

Type:

excretion

Results:

The majority of excretion occured 8 and 24 hours post-dosing (mean values of 82.5 and 88.9 % recovered in the faeces)

Type:

absorption

Results:

Due to the rapid excretion via the faeces, negligible absorption through the GI tract is anticipated.

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Transfer type:

secretion via gastric mucosa

Observation:

no transfer detectable

Remarks:

Almost the entire dose was excreted in the faeces. Most of the remainder was recovered from cage washes and cage debris and suggests that these small amounts were also faecal in origin

Details on excretion:

The analytical results address the rates and routes of excretion of elemental tin after oral administration of a suspension of metallic tin powder with a particle size distribution in the range of 2-11 µm. Lower limits of detection were 0.02 ng/mL for urine (0.02 ppb) and 0.5 µg/mL (0.05 ppm) for all other samples.
Following oral administration of elemental tin powder at a nominal dose level of 2000 mg/kg to male rats, the overall mean recovery was 98.6 % of the administered dose over the 168 hour study period, individual recoveries ranging between 96.9 and 99.7 %. With the exception of minor amounts being recovered in the cage debris and cages washes, most of the tin was recovered in the faeces (mean of 98.3 %, individual recoveries ranging between 96.1 and 99.7 %). It seems likely that the tin recovered in the cage washes and debris was also derived from faecal material. A mean cumulative total of 10.4% of the dosed material was excreted in the faeces during the first 8 hours post dose, rising to 82.5 % at 24 hours and 96.7 % within 48 hours. Most of the remaining dosed material (1.57 %) was also recovered in this matrix. No significant levels of tin were recovered from the male rat that received a single oral administration of the dose vehicle only.
It should be noted that the lower limits of detection were more sensitive for urine analysis and very low, but detectable levels of tin were apparent in this matrix for all of the treated rats. Mean levels of tin reached a peak in the male animals at 24 hours (0.00101 % and remained relatively static at 48 and 72 hours (0.00082 and 0.00088 %, respectively). Thereafter, levels declined reaching 0.00009% at 168 hours post-dose. Over the study period total absorption was <0.004 % of the administered dose. Levels of tin were negligible in the male control animal.
A similar pattern of excretion was noted in the female rats. The mean total recovery of the administered dose was 98.5 % with individual recoveries ranging between 97.7 and 99.6 %. With the exception of a minor amount of tin recovered in the cage washes (<0.1 % of the administered dose) most dosed material was harvested from the faeces. For the females, the highest mean output of dosed material in the faeces was between dosing and 48 hours post-dose (total of 0.01 % at 8 hours, 88.9 % at 24 hours and 98.2 % at 48 hours). No significant levels of tin were detected in the female animal that received a single administration of the dose vehicle alone.
As with the male animals, tin was also detected at low levels in the urine of the females. Mean levels were generally lower than in males, reaching a peak of 0.00059 % at 24 hours and then declining to 0.00017 and 0.00022 % at 48 and 72 hours, respectively. Levels then continued to decline to 0.00003 % of the administered dose at the 168 hours sampling time. Peak levels of tin measured in the urine of the control female animal were also negligible.
Very low, but measurable concentrations of tin in the urine suggest that there may have been some low level of absorption of the dosed material. However, it must also be considered that the urine may have been slightly contaminated by the particularly high levels in the faeces during the collecting process in the metabolism cages.

Metabolites identified:

no

Details on metabolites:

Not relevant for metallic tin

During the course of the study, no overt pharmacological or toxicological signs that could have been attributed to the administration of the test material were observed in the test animals.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results of rapid and almost complete faecal excretion
After administration of elemental tin powder to male and female albino rats, the overall recoveries ranged between 96.9 and 99.7 % of the administered material. Excretion patterns were similar for both male and female animals. Almost the entire administered dose was excreted in the faeces.

Executive summary:

Elemental tin powder was orally administered to male and female albino rats at dose levels up to 2000 mg/kg bw and excreta samples collected over seven days. The overall recoveries ranged between 96.9 and 99.7 % of the administered material. Excretion patterns were similar for both male and female animals. Almost the entire administered dose was excreted in the faeces. The remaining recoveries were considered to arise from faecal contamination of urine, cages or cage wash. The major period for faecal tin output was between 8 and 24 hours post-dosing when mean values of 82.5 and 88.9 % of the dose were recovered for male and female rats respectively.

Small amounts of tin were also recovered in the urine, suggesting that some absorption of test related material may have occurred. However, this small amount could equally be due to cross-contamination from the faeces.

No significant levels of tin were collected from control animals, which received dose vehicle only, suggesting that levels of endogenous material were negligible.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 September 2009 to 17 November 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to other study

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study was designed to determine tin distribution in albino rats following acute oral administration of elemental tin. Analyses were completed using laser ablation and mass spectrometry techniques.
The oral route of administration was the proposed route as this is a key route of exposure in man.

Each animal received a single administration by oral gavage of elemental tin powder (2-11 µm), dosed as a fine suspension in 1 % (w/v) carboxymethyl cellulose (sodium salt), at a nominal dose level of 2000 mg/kg body weight and a dose volume of approximately 10 mL/kg body weight (actual dose volume administered was 11.5 mL/kg bw). Control animals were administered dose vehicle only.

After dosing, single animals of each sex were killed by asphyxiation at 2, 4, 5, 24, 72 and 168 hours. A control animal was concurrently sacrificed at each time point.
Terminal blood samples were collected from each rat. A portion was retained as whole blood and the remainder separated or plasma harvesting.
The GI tract was ligated, removed and separated in to discrete sections for analysis.
The remaining carcass was prepared for whole-body sectioning and prepared samples were forwarded to CAS for analysis.

Samples were analysed for tin concentrations including diet, water, chew blocks, blood, plasma, gut samples and tissues plus whole body sections. Tin analysis was completed by ICP-MS and ICP-ES (Inductively coupled plasma mass spectrometry or inductively coupled plasma emission spectrometry).

GLP compliance:

yes

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl: SD (CD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd, Margate Kent.
- Weight at study initiation: 217 to 258 g (males) and 193 to 216 g (females )
- Housing: Group housed - up to 4 rats per sex in solid floor polycarbonate cages and 3 per sex after dosing.
- Diet: ad libitum SC Rat and Mouse Maintenance Diet No 1, Expanded (Special Diets Services)
- Water: ad libitum mains water via cage bottles
- Acclimation period: 7 days

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

IN-LIFE DATES: From: 18 September 2009 To: 17 November 2009.

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Elemental tin (9.4661 g) was formulated as a fine suspension in 1 % (w/v) carboxymethyl cellulose (sodium salt) to a final weight of 55.67 g. This gave a final concentration of 170 mg/g which was less than the target of 200 mg/g. Consequently the dose volume administerd to aech animal was adjusted from 10 mL/kg bw to 11.5 mL/kg bw.
The formulation was mixed on a magnetic stirrer for about 20 minutes and then left to stand. It was then mixed on a magnetic stirrer immediately before and during the dosing procedure in order to ensure homogeneity.
A single daily preparation on the day of dosing

VEHICLE
- Concentration in vehicle: 170 mg/g
- Amount of vehicle (if gavage): administered at dose volume of 11.5 mL/kg bw

HOMOGENEITY AND STABILITY OF TEST MATERIAL: maintained by continuous stirring and by hand inversion prior to dosing.

Duration and frequency of treatment / exposure:

Single oral administration on day 1

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose / concentration:

Six males and six females treated and one of each sex given vehicle alone as a concurrent control

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

Not applicable

Details on dosing and sampling:

Following a single oral administration, terminal blood samples, tissue samples (including ligated gut with contents), and whole body sections were prepared at each sacrifice point for one rat of each sex (2, 4, 8, 24, 72 and 168 hours post-dosing)

All samples were analysed using Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) or Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES) or Laser Ablation Inductively Coupled Plasma Mass Spectroscopy (LA-ICP-MS).

ICP-MS: blood plasma and drinking water

ICP-AES: gut samples, diet and chew blocks

LA-ICP-MS: tissue samples (adrenal, bone - pelvic; skull; vertebra; femur, bone marrow, brain, brown fat, exorbital lachrymal gland, white fat, intra-orbital lachrymal gland, kidney, lens [eye], liver, lung, lymph nodes, muscle, ovary, prostate, pituitary, salivary glands, seminal vesicles, spinal cord, testis, thymus, thyroid, tongue, uterus ), blood standards and whole body sections.

The lower limit of quantification (LLOQ) was defined as the lowest non-zero standard concentration (0.4752 μg/g) providing it meets the acceptance criteria, sample results falling below the LLOQ are reported as

Statistics:

Not applicable

Preliminary studies:

Not applicable

Type:

distribution

Results:

No body tissues contained detectable levels of tin.

Details on absorption:

Not applicable

Details on distribution in tissues:

Following oral administration of elemental tin powder at a nominal dose level of 2000 mg/kg to rats, the achieved dose was between 1897 and 2060 mg/kg bw.

There were no overt signs of reaction to treatment - no pharmacologcal or toxicological changes attributable to tin administration observed.

In male rats the greatest concentrations (44.2 ng/mL) were detected in the whole blood at the first sampling time (2 hours post-dose). These levels then declined over the study period to 28.5, 11.9, 5.34, 2.98 and 2.78 ng/mL at 4, 8, 24, 72 and 168 hours, respectively.
Levels in plasma were generally lower with a peak at 2 hours of 15.7 ng/mL followed by a small decline to 13.1 ng/mL at 4 hours and a secondary peak of 20.5 ng/mL at 8 hours. Concentrations were then 9.66 ng/mL at 24 hours, but tin levels were below the detection limit (0.02 ng/mL) at 72 and 168 hours.
In females, highest levels of tin in whole blood were 24.4, 27.9 and 24.9 ng/mL at 2, 4 and 8 hours, respectively. Levels then fell to 13.2, 5.40 and 2.85 ng/mL at 24, 72 and 168 hours. Tin concentrations were somewhat lower in the plasma, falling steadily from a peak of 18.8 ng/mL at 2 hours to 0.79 ng/mL at 72 hours. Levels were below the limit of quantification (0.02 ng/mL) at 168 hours.
No tin was detected in the blood or plasma from the control animals that received oral administration of dose vehicle only.

Recovery of Tin from the GI Tract:
The combined mucosa and contents of discrete parts of the GI tract (stomach, small intestine, caecum and large intestine) were analysed for total tin content. For both male and female rats, the distribution of tin in the various parts of the gut generally reflected gut transit time. In male animals 132 and 251 mg of tin were present in the stomach and small intestine, respectively, at 2 hours post-dose with negligible levels in the caecum and nothing at all in the large intestine. By 4 hours, the main bolus of dose had passed further down the gastrointestinal tract with highest levels in the small intestine and caecum (196 and 149 mg of tin, respectively). In comparison, only 32.9 mg were present in the stomach and 50.5 mg in the large intestine. Much of the dose had reached the large intestine at 8 hours (278 mg). Measurements for the stomach, small intestine and caecum were 0.64, 25.8 and 91.4 mg of tin, respectively. Only small amounts of tin were detected in the gastrointestinal tract at 24 hours and beyond and no tin was measurable in the various parts of the gut of the control animal. The distribution of tin in the different parts of the female gastrointestinal tract was very similar to that seen in the males with highest levels in the upper regions at early times and in the lower gut at later times. As with the males, gut transit was almost completed by 24 hours and no tin was measured in the samples harvested from the control female animal.

No measurable tin was detected in samples of diet, water or enrichment chew blocks suggesting no tin was ingested from sources other than the administered dose on Day 1.

Distribution of Tin in Body Tissues
Approximately 25 tissues from each male and female rat were subjected to LA-ICP-MS analysis. In addition to the tissue measurements, representative whole-body sections (one male and one female) prepared for LA-ICP-MS analysis are presented in Figures 2 and 3 of the report.
No tin was measured in any of the tissue samples (the lower limit of detection (LLOQ) was 0.48 µg/g) suggesting that very little was absorbed from the gastrointestinal tract after oral dosing.

Transfer type:

secretion via gastric mucosa

Observation:

other: poorly absorbed from the gastrointestinal tract after oral administration (negligible amounts)

Details on excretion:

Excretion analyses were completed as part of a separate report. The results are presented here for completeness of biodistribution analysis.

The results were prepared based on the CAS Analytical Report (Report Number: AR 75 - attached). The analytical report addresses the rates and routes of excretion of elemental tin after oral administration of a suspension of metallic tin powder with a particle size distribution in the range of 2-11 µm. Lower limits of detection were 0.02 ng/mL for urine (0.02 ppb) and 0.5 µg/mL (0.05 ppm) for all other samples.
Following oral administration of elemental tin powder at a nominal dose level of 2000 mg/kg to male rats, the overall mean recovery was 98.6 % of the administered dose over the 168 hour study period, individual recoveries ranging between 96.9 and 99.7 %. With the exception of minor amounts being recovered in the cage debris and cages washes, most of the tin was recovered in the faeces (mean of 98.3 %, individual recoveries ranging between 96.1 and 99.7 %). It seems likely that the tin recovered in the cage washes and debris was also derived from faecal material. A mean cumulative total of 10.4 % of the dosed material was excreted in the faeces during the first 8 hours post dose, rising to 82.5 % at 24 hours and 96.7 % within 48 hours. Most of the remaining dosed material (1.57 %) was also recovered in this matrix. No significant levels of tin were recovered from the male rat that received a single oral administration of the dose vehicle only.
It should be noted that the lower limits of detection were more sensitive for urine analysis and very low, but detectable levels of tin were apparent in this matrix for all of the treated rats. Mean levels of tin reached a peak in the male animals at 24 hours (0.00101 % and remained relatively static at 48 and 72 hours (0.00082 and 0.00088 %, respectively). Thereafter, levels declined reaching 0.00009 % at 168 hours post-dose. Levels of tin were negligible in the male control animal.
A similar pattern of excretion was noted in the female rats. The mean total recovery of the administered dose was 98.5 % with individual recoveries ranging between 97.7 and 99.6 %. With the exception of a minor amount of tin recovered in the cage washes (<0.1 % of the administered dose) most dosed material was harvested from the faeces. For the females, the highest mean output of dosed material in the faeces was between dosing and 48 hours post-dose (total of 0.01 % percent at 8 hours, 88.9 % at 24 hours and 98.2 % at 48 hours). No significant levels of tin were detected in the female animal that received a single administration of the dose vehicle alone.
As with the male animals, tin was also detected at low levels in the urine of the females. Mean levels were generally lower than in males, reaching a peak of 0.00059 % at 24 hours and then declining to 0.00017 and 0.00022 % at 48 and 72 hours, respectively. Levels then continued to decline to 0.00003 % of the administered dose at the 168 hours sampling time. Peak levels of tin measured in the urine of the control female animal were also negligible.
Very low, but measurable concentrations of tin in the urine suggest that there may have been some low level of absorption of the dosed material. However, it must also be considered that the urine may have been slightly contaminated by the particularly high levels in the faeces during the collecting process in the metabolism cages.

Metabolites identified:

no

Details on metabolites:

No details - metallic tin is not metabolised

The biodistribution of tin was investigated following a single administration of elemental tin powder (2 to 11 µm) to male and female albino rats at a nominal dose level of 2000 mg/kg body weight. Control animals (administered dose vehicle only) were also evaluated and the potential for additional ingestion of tin via food, water or animal enrichment materials was also checked.

Levels of tin measured in the blood ranged between about 3 and 44 ng/mL in both male and female rats with peak levels occurring at the earlier sampling times (between 2 and 8 hours post-dose). Levels of tin in plasma exhibited a similar pharmacokinetic profile, although, in general, concentrations were about half that found in the whole blood. No tin was detected in either the whole blood or plasma of the control animals, which were administered dose vehicle only.

The highest concentrations of tin in the gastrointestinal tract (combined mucosa and content) with time were generally associated with expected gut transit time. In animals of each sex, highest levels of tin were present in the upper gastrointestinal tract (stomach and small intestine) at the earliest sampling time (2 hours) with the main bolus moving steadily down its length thereafter. Highest levels were associated with the large intestine at 8 hours and by 24 hours post-dose the dosed tin was almost entirely eliminated. This was true for both male and female rats. No tin was detected in the gut of the control animals (administered dose vehicle only) suggesting that no tin was ingested from exterior sources. Indeed, the diet, water and enrichment materials given to the animals were also evaluated for tin and none was found.

Laser ablation of tissues (approximately 25 tissues/animal) from whole-body sections followed by subsequent analysis by ICP-MS indicated that no measurable tin was present.

In general, it was apparent that the administered tin was only poorly absorbed from the gastrointestinal tract after oral administration. Although measurable amounts were detected in blood and plasma, it should be noted that sensitivity of the assay used (ICP-MS) was far better (0.02 ng/mL) than that used for other samples (mg range for gastrointestinal samples and 0.48 µg/g for tissues by laser ablation). Thus, no tin was measurable in any of the tissues from the whole-body sections.

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results; None of the tissues analysed contained detectable levels of tin following dosing at 2000 mg/kg bw.
In general, it was apparent that the administered tin was only poorly absorbed from the gastrointestinal tract after oral administration. Although measurable amounts were detected in blood and plasma, it should be noted that sensitivity of the assay used (ICP-MS) was far better (0.02 ng/mL) than that used for other samples (mg range for gastrointestinal samples and 0.48 μg/g for tissues by laser ablation). Thus, no tin was measurable in any of the tissues from the whole-body sections.

• After administration of elemental tin powder to male and female albino rats, low, but detectable levels of tin were apparent in the whole blood and plasma
• Various regions of the gastrointestinal tract contained high concentrations of tin after dosing, but levels in individual regions were generally indicative of normal gut transit
• Environmental enrichment material, diet and drinking water contained no detectable endogenous tin
• No body tissues contained detectable levels of tin

Executive summary:

The biodistribution of tin was investigated following a single administration of elemental tin powder (2 to 11 µm) to male and female rats at a nominal dose level of 2000 mg/kg bw. Control animals (administered dose vehicle only) were also evaluated and the potential for additional ingestion of tin via food, water or animal enrichment materials was also checked.

Levels of tin measured in the blood ranged between about 3 and 44 ng/mL in both male and female rats with peak levels occurring at sampling times between 2 and 8 hours post-dose. Tin levels in plasma exhibited a similar pharmacokinetic profile, although, in general, concentrations were about half those found in whole blood. No tin was detected in either the whole blood or plasma of the control animals.

The highest concentrations of tin in the gastrointestinal tract (combined mucosa and content) were generally corrollated with expected gut transit time. Highest levels of tin were present in the upper gastrointestinal tract (stomach and small intestine) at the earliest sampling time (2 hours) with the main bolus moving steadily down the gut such that highest levels after 8 hours were associated with the large intestine and by 24 hours post-dose the administered tin was almost entirely eliminated in both sexes. No tin was detected in the gut of the control animals suggesting that no tin was ingested from exterior sources. Analysis of the diet, water and enrichment materials given to the animals resulted in no tin being detected.

Laser ablation of tissues from whole-body sections followed by subsequent analysis by ICP-MS indicated that no measurable tin was present.

In general, it was apparent that the administered tin was only poorly absorbed from the gastrointestinal tract after oral administration. Although measurable amounts were detected in blood and plasma, it should be noted that sensitivity of the assay used (ICP-MS) was far better (0.02 ng/mL) than that used for other samples (mg range for gastrointestinal samples and 0.48 µg/g for tissues by laser ablation). Thus, no tin was measurable in any of the tissues from the whole-body sections. In the excretion study, very low levels of tin were detected in urine, although it was not clear if this was attributable to faecal contamination. Taken together with the biodistribution study results, it seems likely that very small amounts of tin may be absorbed during transit through the GI tract. In previous studies it has been suggested that tin metal may cause some gut irritation or even gastroenteritis. The data supporting the case are weak and the miniscule amounts of tin absorbed in the gut in this study would suggest that no disturbance of the gastrointestinal mucosa occurs. Given the low absorption it is also unlikely that any significant protein binding is occurring and it does not appear that significant amounts of tin are bound to metallothionein or replacing, for example zinc, in protein complexes for absorption through the gut mucosa.

Description of key information

Tin metal is insoluble and not bioavailable. It is rapidly excreted via faeces following ingestion and has been found not to accumulate in tissues.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

0.004

Absorption rate - dermal (%):

0.004

Absorption rate - inhalation (%):

0.004

Additional information

Assessment of physicochemical properties of a substance can shed light on a number of important points when assessing the toxicological profile of a substance. From the vapour pressure, it is clear that tin would only present an inhalatory hazard if rendered to a fine dust, furthermore, assessment of the solubility of the substance indicates that it is poorly soluble in various solvents (water solubility considered to be considerably less than 0.004 mg/L, which was the limit of detection used in the OECD 105 water solubility study), and would have a low potential for absorption via all routes. As the registered substance is pure tin, the 0 valence state indicates a low potential for biochemical interaction.

 

Oral absorption, distribution, metabolism and excretion

Two toxicokinetic studies were available for assessment (Whitby, 2010 a,b). Both studies were performed to a good scientific standard. Both studies dosed rats with a single oral dose (2000 mg/kg bw) of fine tin powder (2 -11 microns), one to measure excretion, the other to study distribution. The excretion study (Whitby, 2010a) demonstrated that nearly all of the dose (>99 %) was recoverable from the faeces, with a small amount recovered from the urine. Although it was not possible to rule out some cross contamination in collection of excreta, detectable plasma concentrations in the distribution study (Whitby, 2010b) indicate that urinary excretion in the excretion study (Whitby 2010a) was most likely from material absorbed from the gut. The amounts considered absorbed in the distribution and excretion studies, although detectable using ICP-MS (an extremely sensitive technique compared to other conventional methods) were negligible compared to the size of the dose and surface area of material (<0.004 % of administered dose). This is further supported by the rapid excretion of tin with the majority of the dose recovered between 8 and 24 hours. The virtual lack of absorption observed in the excretion study was further supported by the results of the biodistribution study which determined that tin was not retained in tissues (especially in bone where accumulation would be expected), suggesting little or no metallothionein binding.

No studies addressing the metabolism of inorganic tin were found. However, metallic elemental tin is not capable of undergoing metabolic breakdown in a manner analogous to organic test materials and so such studies would not be expected.

In addition to the toxicokinetics studies, the acute and repeated dose toxicity studies via the oral route support relative absence of absorption and a lack of toxic effects.

 

Overall it should be remembered that the studies provided represent an extreme worst-case for estimation of absorption; despite the rats receiving a very large dose of very finely divided tin powder absorption was comparatively very low. The material used was not representative of the material used in Europe which is coarser. Under realistic oral exposure scenarios it is not expected that tin would be detectable in plasma: ECHA itself noted (in its draft decision of 6th March 2014) that the biodistribution study shows tin concentrations in the blood of rats up to 44 ng/mL, and subsequently put these into context of normal human background plasma concentrations of 2 -9 ng/mL citing a WHO publication (Tin and Inorganic Tin Compounds, Cicad 65, 2005), which also cited the normal background dietary consumption of tin to be <1 up to 15 mg/day per person (equivalent of up to 0.25 mg/kg bw/day). Increasing the exposure 8000 times in the biodistribution study only increased plasma concentrations 5 times. Given maximum occupational exposures equate to considerably less than 1 mg/kg bw/day from inhalation and dermal routes, there would therefore be no discernible contribution of occupational exposure to tin powder to plasma concentrations, and absorption for practical purposes can be considered zero [see the CSR - highest anticipated inhalation exposure without PPE or engineering control is typically 4-5 mg/m3, peaking at 10 mg/m3, whilst dermally it is up to 9.9 mg/day. Engineering controls or PPE will be required to reduce this to comply with non-specific nuisance dust rules (the OEL for non-specific nuisance dust is frequently specified as 10 mg/m3 total inhalable and/or with a respirable fraction no greater than 3 mg/m3), hence these exposures will be considerably lower. There is no anticipated consumer exposure where tin is in solid metallic form either pure or in an alloy.].

 

Material which was absorbed in the rat studies is considered to be that which is dissolved from the powdered metal in the gut. Based on the results of the excretion study, oral absorption from a 2000 mg/kg dose of powdered tin with a very large surface area (particles 2 -11 microns), even after exposure to acid conditions in the stomach, was estimated at <0.004 % of the total administered dose. This very conservative value will be used for starting point correction purposes, but for risk assessment purposes absorption of tin metal is considered to be zero.

 

Dermal absorption

No studies were performed examining dermal absorption, however, due to the limited solubility of the substance, limited dermal absorption is expected, if any. Based on the premise that dermal absorption cannot be greater than oral absorption, for the purposes of correction of starting point, dermal absorption is also considered to be <0.004 %, but for risk assessment purposes absorption of tin metal under normal occupational exposure conditions can be considered zero.

 

Inhalation absorption

An acute inhalation toxicity study (Parcell, 1994) was performed. Deposition of the test material was noted throughout the respiratory tract, however, no toxic effects were noted. Based on the images of the photomicrograph report accompanying the study, it is evident that clearance is observed within the 14 day observation period, with the most and likely route of clearance being the mucocilliary escalator and subsequently swallowed. The particles used would not be able to penetrate lung tissue on their own, but were small enough for phagocytosis by macrophages patrolling the external epithelial surfaces of the alveoli and bronchioles, the predominant fate of which is also to be cleared via the mucocilliary escalator to the gastro-intestinal tract (GIT).

 

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.

 

In one male (out of four animals examined) 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. The origin of these sub-epithelial particles is likely to be impaction of the particles on the bifurcation point on inhalation (Impaction occurs at airway bifurcations when a particle, owing to its momentum and the aerodynamic forces exerted on it by the stream of air in which it is carried, fails to make the turn into either of the daughter branches and impacts on the bifurcation). In the case of this study exposure to the tin was extreme (4750 mg/m3) when compared to general occupational OEL for non-specific nuisance dust, frequently specified as 10 mg/m3 total inhalable and/or with a respirable fraction no greater than 3 mg/m3, depending on the member state.

 

There were no other microscopic findings due to effects of the test article including inflammation. Overall given the absence of any indication of the particles to be able to cross the lung epithelia, absorption of the metallic particles in the lung is unlikely to be any greater than via the GIT, hence for the purposes of correction of starting point, inhalation absorption is also considered to be <0.004 %, but for risk assessment purposes absorption of tin metal under normal occupational exposure conditions can be considered zero.