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Toxicological information

Basic toxicokinetics

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Objective of study:
excretion
Test guideline
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Elemental tin powder (2-11 µm)
- Substance type: metallic tin powder
- Physical state: powder
- Analytical purity: 99.97 %
- Lot/batch No.: 070402
- Expiration date of the lot/batch: 5 March 2009
- Stability under test conditions: stable at room temperature
- Storage condition of test material: room temperature 15-25 °C
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Sprague-Dawley Crl: SD (CD)
Sex:
male/female
Details on test animals 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.

Administration / exposure

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
Doses / concentrations
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
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))

Results and discussion

Main ADME resultsopen allclose all
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.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not applicable
Details on distribution in tissues:
Not applicable
Transfer into organs
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.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Not relevant for metallic tin

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.