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Repeated dose toxicity: inhalation

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Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2015
Reliability:
other: significant variance in dose and humidity
Rationale for reliability incl. deficiencies:
other: significant variance in dose and humidity, only evaluation of study based on raw data possible
Cross-reference
Reason / purpose for cross-reference:
reference to other study
Remarks:
corresponding Dose-reange finder
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
12 August 2014 - 13 November 2014
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
reference to other study
Remarks:
main study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Due to the preliminary nature of this study no specific regulations or guidelines are applicable.
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material:
- Purity, including information on contaminants, isomers, etc.:

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity:
- Specific activity:
- Locations of the label:
- Expiration date of radiochemical substance:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage:
- Stability in the medium, i.e. sensitivity of the test material to hydrolysis and/or photolysis:
- Solubility and stability of the test material in the solvent/vehicle and the exposure medium:
- Reactivity of the test material with the incubation material used (e.g. plastic ware):

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing (e.g. warming, grinding):
- Preliminary purification step (if any):
- Final concentration of a dissolved solid, stock liquid or gel:
- Final preparation of a solid (e.g. stock crystals ground to fine powder using a mortar and pestle):

FORM AS APPLIED IN THE TEST (if different from that of starting material)
- Specify the relevant form characteristics if different from those in the starting material, such as state of aggregation, shape of particles or particle size distribution:

INFORMATION ON NANOMATERIALS
- Chemical Composition:
- Density:
- Particle size & distribution:
- Specific surface area:
- Isoelectric point:
- Dissolution (rate):

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)
- Description of the formulation, e.g. formulated product for foliar application; formulated product soil application; solution in organic solvent for soil application; formulated product seed treatment; solution in organic solvent seed treatment:

OTHER SPECIFICS
- Other relevant information needed for characterising the tested material, e.g. if radiolabelled, adjustment of pH, osmolality and precipitate in the culture medium to which the test chemical is added:
Species:
rat
Strain:
Wistar
Remarks:
RccHan(TM) Wistar rats
Details on species / strain selection:
Strain/Species RccHan™:WIST rat.
Supplier: Harlan (UK) Ltd
Sex:
male/female
Details on test animals or test system and environmental conditions:
Strain/Species RccHan™:WIST rat.
Supplier: Harlan (UK) Ltd
Number of animals: 15 males and 15 females.
Spare animals were removed from the study room after treatment commenced.
Duration of acclimatisation: 11 days before commencement of treatment.
Age of the animals at start of treatment: 61 to 67 days old.
Weight range of animals at the start of treatment: Males: 225 to 260 g, Females: 159 to 181 g

Allocation: Randomly allocated on arrival.
Using the sequence of cages in the battery, one animal at a time was placed in each cage with the procedure being repeated until each cage held the appropriate number of animals. Each sex was allocated separately.
Identification of animals: Each animal was assigned a number and identified uniquely within the study by a microchip inserted shortly after arrival.
Identification of cages: Each cage label was colour-coded according to group and was numbered uniquely with cage and study number, as well as the identity of the occupants.

Animal housing, diet and water supply
Environmental. control
Rodent facility Restricted entry - to minimise entry of external biological and chemical agents and to minimise the transference of such agents between r.ooms.
Air supply Filtered fresh air which was passed to atmosphere and not recirculated.

Temperature and relative humidity
Monitored and maintained within the range of 19-23 ºC and 40-70 %.
There were no deviations from these ranges.
Lighting: Artificial lighting, 12 hours light: 12 hours dark.
Electricity supply: Public supply with automatic stand-by generators.

Animal accommodation: Cages Polycarbonate body with a stainless steel mesh lid, changed at appropriate intervals.
Cage distribution: The cages constituting each group were blocked together by sex on separate batteries.
Number of animals per cage: Three of the same sex.

Bedding: Wood based bedding which was changed at appropirate intervals each week.

Environmental enrichment
Aspen chew block: Provided to each cage throughout the study and replaced when necessary.
Plastic shelter: Provided to each cage throughout the study and replaced when necessary.

Diet supply
Diet: Rat and Mouse No. 1 Maintenance Diet.
Availability: Non-restricted (removed overnight before blood sampling for haematology or blood chemistry, urine collection and during dosing).

Water supply
Supply: Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals.
Availability: Non-restricted (except during urine collection and dosing).
Route of administration:
inhalation: dust
Type of inhalation exposure:
snout only
Vehicle:
air
Mass median aerodynamic diameter (MMAD):
>= 3.2 - <= 4.8 µm
Geometric standard deviation (GSD):
2.58
Remarks on MMAD:
Group 2 - Target concentration = 2.3 µg/L - Achieved Exposure level = 2.28 µg/L = MMAD = 4.8 µm - geometric standard diameter = 2.74
Group 3 - Target concentration = 9.1 µg/L - Achieved Exposure level = 10.6 µg/L = MMAD = 3.2 µm - geometric standard diameter = 2.51
Group 4 - Target concentration = 36.3 µg/L - Achieved Exposure level = 41.8 µg/L = MMAD = 3.2 µm - geometric standard diameter = 2.49

The achieved levels were 99, 116 and 115 % of the target concentrations for Groups 2, 3 and 4 respectively. The MMAD values for Groups 3 and 4 are slightly above the ideal range of 1 to 3 μm with 79 to 80 % of the particles within the respirable range (< 7 μm). The Group 2 MMAD value was higher with a lower percentage of particles within the respirable range (64 %).
Details on inhalation exposure:
The animals on study were acclimated to the method of restraint, over a 5 day period immediately preceding the first test substance exposure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Mass Median Aerodynamic Diameter:
The MMAD values for Groups 3 and 4 are slightly above the ideal range of 1 to 3 μm with 79 +/- 80 % of the particles within the respirable range (<7 μm). A jet mill was used for Groups 3 and 4 to reduce the average particle size, however it was not practical to fit a jet mill on the Group 2
system, this is considered to be the reason for the higher MMAD value of 4.8 μm and lower percentage of particles within the respirable range (64 %).
Duration of treatment / exposure:
6 h/day
Frequency of treatment:
5
Dose / conc.:
2.28 mg/m³ air (analytical)
Remarks:
(nominal: 2.3 µg/L = 2.3 mg/m³)
Dose / conc.:
10.6 mg/m³ air (analytical)
Remarks:
(nominal: 9.1 µg/L = 9.1 mg//m²)
Dose / conc.:
41.8 mg/m³ air (analytical)
Remarks:
(nominal: 36.3 µg/L = 36.3 mg/m³)
No. of animals per sex per dose:
3
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment (if not random):
- Fasting period before blood sampling for clinical biochemistry: yes (12 hours)
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random):

This study was designed to assess the systemic toxic potential of tin monoxide in a 1 week (6 hours per day, 5 days a week) inhalation study in RccHan™;WIST rats.
The study design was as follows: Group 1 - Control - 0 µg/L (3 males & 3 females), Group 2 - Tin Monoxide - 2.3 µg/L - (3 males & 3 females), Group 3 - Tin Monoxide - 9.1 µg/L (3 males & 3 females), Group 4 - Tin Monoxide - 36.3 µg/L (3 males & 3 females)
Animals received air only or the test substance, tin monoxide by inhalation for 1 week (6 hours per day, 5 days a week).
During the study, clinical condition, body weight, food consumption, haematology (peripheral blood), blood chemistry, urinalysis, bioavailability, blood oxygen saturation, organ weight, macropathology and histopathology investigations were undertaken.
Positive control:
none
Observations and examinations performed and frequency:
Clinical observations:
Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupants.
Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.
During the acclimatisation period, observations of the animals and their cages were recorded at least once per day.

Signs associated with dosing:
Detailed observations were recorded daily at the following times in relation to dose administration:
- Pre-exposure observation
- During exposure however, observation is severely restricted due to tube restraint
- As each animal is returned to its home cage
- As late as possible in the working day

Clinical signs: A detailed weekly physical examination was performed on each animal to monitor general health.

Body weight: The weight of each animal was recorded daily from Day -5 (Day P3), throughout the study and before necropsy.

Food consumption: The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded daily from Day -5 (Day P3) throughout the study.

Haematology, peripheral blood:
Blood samples were collected after overnight withdrawal of food and prior to dosing (where appropriate) at the following occasion: Week 1: All animals.
Animals were held under light general anaesthesia induced by isoflurane. Blood samples (nominally 0.3 mL) were withdrawn from the sublingual vein, collected into tubes containing EDTA anticoagulant and examined for the following characteristics using a Bayer Advia 120 analyser: Haematocrit (Hct), Haemoglobin concentration (Hb), Erythrocyte count (RBC), Absolute reticulocyte count (Retic), Mean cell haemoglobin (MCH), Mean cell haemoglobin concentration (MCHC), Mean cell volume (MCV), Red cell distribution width (RDW), Total leucocyte count (WBC),
Differential leucocyte count: Neutrophils (N), Lymphocytes (L), Eosinophils (E), Basophils (B), Monocytes (M), Large unstained cells (LUC)
Platelet count (Plt)
Morphology:,Anisocytosis, Macrocytosis, Microcytosis, Hypochromasia, Hyperchromasia
Blood film (prepared for all samples) - Romanowsky stain, examined for abnormalities by light microscopy, in the case of flags from the Advia 120 analyser. Confirmation or a written description from the blood film was made where appropriate.
Additional blood samples (nominally 0.5 mL) were taken into tubes containing citrate anticoagulant and examined using an ACL series analyser and appropriate reagent in respect of:
- Prothrombin time (PT) - using IL PT-Fibrinogen reagent.
- Activated partial thromboplastin time (APTT) - using IL APTT reagent.

Haematology, bone marrow: Bone marrow smears were prepared immediately following death on completion of the scheduled treatment period.
Fixation: Smears were air dried and subsequently fixed in methanol.
Retention Slides were retained by the Department of Biomarkers, Bioanalysis and Clinical Sciences.
Analysis: At the discretion of the pathologist, examination of smears to further evaluate other findings was not considered necessary; the smears are retained in the archives.

Blood chemistry: Blood samples were collected after overnight withdrawal of food and prior to dosing (where appropriate) at the following occasions:
Occasion Animals: Week 1 - All animals

Animals were held under light general anaesthesia induced by isoflurane. Blood samples (nominally 0.5 mL, Groups 2 and 3 and 0.6 mL Groups 1 and 4) were withdrawn from the sublingual vein and collected into tubes containing lithium heparin as anticoagulant. After separation, the plasma was examined using a Roche P Modular Analyser in respect of: Alkaline phosphatase (ALP); Alanine aminotransferase (ALT); Aspartate aminotransferase (AST), Gamma-glutamyl transpeptidase (gGT), Total bilirubin (Bili), Urea, Creatinine (Creat), Glucose (Gluc), Total cholesterol (Chol), Triglycerides (Trig), Sodium (Na), Potassium (K), Chloride (Cl), Calcium (Ca), Inorganic phosphorus (Phos), Total protein (Total Prot), Albumin (Alb), Copper (CU) – Groups 1 and 4 only (non-GLP), Iron (Fe).

Albumin/globulin ratio (A/G Ratio) was calculated from total protein concentration and analysed albumin concentration.

Urinalysis
Animals were placed in an individual metabolism cage overnight, without food or water. Urine samples were collected over approximately 16 hours at the following occasion: Week 1 - All animals
The individual samples were examined for the following characteristics:
Using manual methods:
- Clarity and Colour (App) - by visual assessment
- Volume (Vol) - using a measuring cylinder
- pH - using a pH meter
- Specific gravity (SG) - by direct refractometry using a SG meter

Using Multistix reagent strips, interpreted using a Clinitek®500 instrument: Ketones (Keto); Bilirubin/bile pigments (Bili); Blood pigments (UBld);
Using a Roche P Modular analyser: Protein (T-Prot); Creatinine (T-Creat); Glucose (T-Gluc)
Sacrifice and pathology:
Terminal Procedures
All animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
The retained tissues were checked before disposal of the carcass.
Schedule: Study animals were killed following treatment on Day 5.
Method of kill: Overdose of intraperitoneal pentobarbitone sodium followed by exsanguination.
Sequence: To allow satisfactory inter-group comparison.
The organs weighed, tissue samples fixed and sections examined microscopically are detailed as detailes in the field Any other information on materials and methods

Organ weights
For bilateral organs, left and right organs were weighed together, unless specified above.
Requisite organs were weighed for study animals killed at scheduled intervals.

Fixation
Tissues were routinely preserved in 10% Neutral Buffered Formalin with the exception of those detailed below:
Testes: In modified Davidson’s fluid.
Eyes: In Davidson’s fluid.
Bone marrow smears: See below.

Histology
Processing Tissue samples were dehydrated, embedded in paraffin wax and sectioned at a nominal four to five micron thickness. A single section was prepared from each of the tissues required.
Full List All animals killed or dying prematurely.
Study animals of Groups 1 and 4 killed at the scheduled necropsy.
Routine staining Sections were stained with haematoxylin and eosin.

Light microscopy
Tissues preserved for examination were examined as follows:
Category: Scheduled kill - Animals: All animals of Groups 1 and 4, Tissues: All specified
Findings were either reported as "present" or assigned a severity grade. In the latter case one of the following five grades was used - minimal, slight, moderate, marked or severe. A reviewing pathologist undertook a peer review of the microscopic findings.
Other examinations:
Bioavailability (Non-GLP)
The sampling schedule was as follows: At termination Group 1 and Group 4: Time of sampling (hours after completion of dosing): 2 hours; Parameter: Tin
Samples were collected under terminal anaesthesia.
Blood sample site: Cardiac puncture.
Anaesthetic: Isoflurane.
Anticoagulant: Lithium heparin.
Blood volume: 0.6 mL.
Treatment of samples: Gently inverted several times and then placed on an automatic mixer for at least 2 minutes continuously at ambient temperature.
Centrifugation conditions At 1300 g for 10 minutes at 21 °C.
Number of aliquots per sample: One
Temporary storage conditions: Plasma was processed at ambient temperature and stored frozen (approximately -20 ˚C) as soon as practicable following completion of blood sampling completion of blood sampling
Final storage conditions: Deep frozen (approximately -20 ºC).
Fate of plasma samples: Despatched to a Responsible Scientist on solid carbon dioxide.

Blood oxygen saturation
The sampling schedule was as follows: at Day 5 Group 1 and Group 4 animals
Blood sample site: Tail vein.
Anticoagulant: Lithium heparin.
Blood volume: 0.3 mL.
Samples were analysed without delay.
Each sample was used to measure the following parameter using a blood gas analyser system (ABL80 CO-OX FLEX).
-- Oxygen saturation (sO2)
Statistics:
All statistical analyses were carried out separately for males and females using the individual animal as the basic experimental unit.
The following data types were analysed at each timepoint separately:
- Body weight, using gains over appropriate study periods
- Haematology
- Blood chemistry
- Urinalysis
- Organ weights, absolute and adjusted for terminal body weight
Clinical signs:
no effects observed
Description (incidence and severity):
There were no treatment related clinical signs observed during the detailed weekly physical examination.
Signs associated with the administration procedure included wet fur and red staining of the head on return to the home cage. These signs are associated with the method of restraint used.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related changes in body weights.
There was a body weight loss for all animals on Day 4. This is considered due to all animals having food and water withdrawn overnight on Day 3 for blood and urine sampling. Body weight gains were evident for all animals on Day 5.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no treatment related changes in food consumption.
Reduced food consumption was evident for all animals from Days 3 to 4. This is considered due to all animals having food withdrawn overnight on Day 3 for blood and urine sampling. Food consumption had recovered for all animals on Days 4 to 5.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
Group mean neutrophil counts were statistically significantly high for males exposed to 41.8 μg/L (1.8X control values). Neutrophil counts were also high for males and females exposed to 2.28, 10.6 μg/L. However, a few individual values for each sex, in each group, were close to control values. Due to the lack of a dose-related response in females, it is not considered a treatment related effect in females.
Other changes from control were small, inconsistent between sexes and/or did not show clear dose relationships.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Group mean inorganic phosphorus levels where high for males exposed to 41.8 μg/L (1.3X control values) and all females exposed to tin monoxide (1.3X, 1.3X and 1.4X control values for females exposed to 2.28, 10.6 and 41.8 μg/L respectively), all attaining statistical significance.
Other changes from control including those that attained statistical significance, were small, inconsistent between sexes and/or did not show clear dose relationships.
Endocrine findings:
not examined
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no treatment related effects on urinalysis parameters.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Group mean body weight adjusted lung and bronchi weights were statistically significantly high for females exposed to 10.6 and 41.8 μg/L (both 1.2X control values).
Group mean body weight adjusted spleen weights were higher for all males exposed to tin monoxide (1.2, 1.4 and 1.3X control values for males exposed to 2.28, 10.6 and 41.8 μg/L respectively), with males exposed to 41.8 μg/L attaining statistical significance.
All other differences from control including those that attained statistical significance, were generally small and are not considered to be of toxicological significance.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The macroscopic examination performed after 1 week of treatment revealed the followingbchanges in the tracheobronchial lymph nodes.
Tracheobronchial lymph nodes
Enlargement was seen in two male animals treated with 41.8 μg/L, one female animal treated with 2.28 μg/L and one female animal treated with 10.6 μg/L.
The nature and incidence of all other findings were consistent with the commonly seen background of macroscopic changes and were considered to be unrelated to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Treatment related findings
There were no microscopic findings that were considered to be related to treatment with tin monoxide.

Incidental findings
All histological changes were considered to be unrelated to treatment.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Blood oxygen saturation levels appeared to be lower than control values for all males exposed to 41.8μg/L. However, the blood gas analyser reported that there were errors which may have affected the results for two of the males exposed to 41.8 μg/L (animal numbers 10 and 11). For the remaining male exposed to 41.8μg/L, the blood oxygen saturation level was lower than control (approximately 0.7X). Blood oxygen saturation levels for females exposed to 41.8 μg/L were all similar to control values.

Bioavailability (non-GLP): Tin concentrations in plasma for controls were all below the limit of quantification (< 5 ng/mL) for the test analysis. Tin concentrations in plasma for males and females exposed to 41.8 μg/L were all approximately 2-3X greater than the lower limit of quantification.
Dose descriptor:
NOAEL
Effect level:
> 41.8 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: The exposure was well tolerated and resulted in no adverse findings.

Discussion

The test article, tin monoxide, was administered by snout-only inhalation administration, for 6 hours a day for 5 consecutive days, at achieved exposure levels of 2.28, 10.6 and 41.8 μg/L. There were no unscheduled deaths or treatment related effects on clinical signs, body weight, food consumption, urinalysis parameters and histopathology findings. Slightly higher body weight adjusted lung and bronchi weights were evident for females exposed to 10.6 and 41.8 μg/L. In the absence of a similar effect in males or any correlating histopathological changes, these were considered to be of no toxicological importance. Slightly higher body weight adjusted spleen weights were evident for all males exposed to tin monoxide.

Whilst histopathological correlates for these changes could not be made as spleens were not examined microscopically, the absence of any corresponding macropathology or clinical pathology changes, this is not considered to be related to treatment.

Analysis of tin monoxide concentrations in plasma for males and females exposed to 41.8 μg/L indicated that the test article was present in plasma 2 hours after the completion of exposures.

However, this work was not performed to the principles of GLP and as such, no formal conclusions can be drawn from this data.

A reduction in blood oxygen saturation levels was observed in one male exposed to 41.8 μg/L. However, due to the lack of conclusive results from the remaining two males exposed to 41.8 μg/L, a relationship to treatment cannot be confirmed for males. Blood oxygen saturation results for females were similar to control values.

An increase in neutrophil counts was evident for males exposed to 41.8 μg/L. The slight increases in inorganic phosphorous levels for males exposed to 41.8 μg/L, and all females exposed to tin monoxide, were of uncertain relationship to treatment.

Conclusion

It is concluded that snout only exposure to tin monoxide to RccHan™;WIST rats for six hours each day for five days, at achieved exposure levels of 2.28, 10.6 or 41.8 μg/L, was well tolerated and resulted in no adverse findings. The results therefore demonstrate that exposing animals to at least the same exposure levels that were used in this study would be suitable for use in a four week toxicity study.

Conclusions:
Snout only exposure to tin monoxide to RccHan™;WIST rats for six hours each day for five days, at achieved exposure levels of 2.28, 10.6 or 41.8 μg/L, was well tolerated and resulted in no adverse findings.
Executive summary:

This study was designed to assess the systemic toxic potential of tin monoxide in a 1 week (6 hours per day, 5 days a week) inhalation study in RccHan™;WIST rats. It was conducted as a Dose-range finder for the envisaged OECD 412, which was then conducted.

The study design was as follows: Group 1 - Control - 0 µg/L (3 males & 3 females), Group 2 - Tin Monoxide - nominal 2.3 µg/L = analytically verifeid 2.28 µg/L (3 males & 3 females), Group 3 - Tin Monoxide - nominal 9.1 µg/L = analytically verified 10 .6 µg/L (3 males & 3 fenales), Group 4 - Tin Monoxide - nominal 36.3 µg/L = analytically verified 41.8 µg/L (3 males & 3 females). Animals received air only or the test substance, tin monoxide by inhalation for 1 week (6 hours per day, 5 days a week).

During the study, clinical condition, body weight, food consumption, haematology (peripheral blood), blood chemistry, urinalysis, bioavailability, blood oxygen saturation, organ weight, macropathology and histopathology investigations were undertaken.

Concernign the Mass Median aerodynamic diameter, the following is reported: Group 2 - Target concentration = 2.3 µg/L - Achieved Exposure level = 2.28 µg/L = MMAD = 4.8 µm - geometric standard diameter = 2.74, Group 3 - Target concentration = 9.1 µg/L - Achieved Exposure level = 10.6 µg/L = MMAD = 3.2 µm - geometric standard diameter = 2.51, Group 4 - Target concentration = 36.3 µg/L - Achieved Exposure level = 41.8 µg/L = MMAD = 3.2 µm - geometric standard diameter = 2.49, The achieved levels were 99, 116 and 115 % of the target concentrations for Groups 2, 3 and 4 respectively. The MMAD values for Groups 3 and 4 are slightly above the ideal range of 1 to 3 μm with 79 to 80% of the particles within the respirable range (<7 μm). The Group 2 MMAD value was higher with a lower percentage of particles within the respirable range (64 %).

Group mean body weight adjusted lung and bronchi weights high for females exposed to 10.6 and 41.8 μg/L. Group mean body weight adjusted spleen weights were higher for all males exposed to tin monoxide.

Compared with control, higher group mean neutrophil counts was evident for males exposed to 41.8 μg/L. Compared with control, higher group mean inorganic phosphorous levels were evident for males exposed to 41.8 μg/L and all females exposed to tin monoxide. Group mean body weight adjusted lung and bronchi weights were statistically significantly high

for females exposed to 10.6 and 41.8 μg/L. Group mean body weight adjusted spleen weights were higher for all males exposed to tin monoxide. Enlargement of the tracheobronchial lymph nodes was evident for two males exposed to

41.8 μg/L, one female exposed to 2.28 μg/L and one female exposed to 10.6 μg/L. Tin was present in plasma 2 hours after the completion of dosing for all male and female animals exposed to 41.8 μg/L. However, this work was not performed to GLP.

Conclusion

It is concluded that snout only exposure to tin monoxide to RccHan™;WIST rats for six hours each day for five days, at achieved exposure levels of 2.28, 10.6 or 41.8 μg/L, was well tolerated and resulted in no adverse findings. The results therefore demonstrate that exposing animals to at least the same exposure levels that were used in this study would be suitable for use in a four week toxicity study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Principles of method if other than guideline:
significant variance in dose and humidity
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tin monoxide
EC Number:
244-499-5
EC Name:
Tin monoxide
Cas Number:
21651-19-4
Molecular formula:
OSn
IUPAC Name:
Tin monoxide
Test material form:
other: dust

Test animals

Species:
rat
Strain:
other: RccHan™:WIST rat.
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Remarks on MMAD:
MMAD / GSD: see raw data
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 h exposure
Frequency of treatment:
5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
2.3 mg/m³ air (nominal)
Remarks:
achieved 2.44 µg/L
Dose / conc.:
9.1 mg/m³ air (nominal)
Remarks:
achieved 9.19 µg/L
Dose / conc.:
80 mg/m³ air (nominal)
Remarks:
achieved 87.9 µg/L
No. of animals per sex per dose:
see raw data
Control animals:
yes

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

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