Tin dioxide

Endpoint summary

Description of key information

Oral, LD50 > 2,000 mg/kg bw, rat (EU Method B1)
Inhalation, LC50 > 2.04 mg/L, rat (OECD 403, EU method B2)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 3rd to 17th August 1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented GLP study.

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Equal numbers of healthy male and female CD rats of Sprague-Dawley origin (Hsd/Ola:SpragueDawley(CD)) were obtained from Harlan Olac Ltd., Bicester, Oxon, England.
They were in the weight range of 97 to 114 g and approximately four to seven weeks of age prior to dosing (Day 1) in the main study. All the rats were acclimatised to the experimental environment for a period of six days prior to the start of the main study.
The rats were allocated without conscious bias to cages within the treatment group. They were housed in groups of up to five rats of the same sex in metal cages with wire mesh floors in Building R14 Room 6.
A standard laboratory rodent diet and drinking water were provided ad libitum.
Access to food only was prevented overnight prior to and approximately 4 hours after dosing.
The batch(es) of diet used for the study was analysed for certain nutrients, possible contaminants and micro-organisms.
Animal room temperature was set to achieve a temperature of 22 ± 3°C.
Relative humidity was not controlled but was anticipated to be in the range 30 - 70% R.H.
Permanent daily recordings of these parameters was made and these are archived with other Department raw data. Any slight deviation in temperature and humidity that may have occurred had no impact on the study in the opinion of the Study Director. Air exchange was maintained at 10 to 15 air changes per hour and lighting controlled by means of a time switch to provide 12 hours of artificial light (0700 - 1900 hours) in each 24-hour period.

Route of administration:

oral: gavage

Vehicle:

other: methylcellulose

Details on oral exposure:

The appropriate dose volume of the test substance was administered to each rat by oral gavage using a syringe and plastic catheter (8 choke).
The day of dosing was designated Day 1.

Doses:

Anhydrous stannic oxide (SnO2) was prepared at a concentration of 20% w/v in 1% w/v aqueous methylcellulose and administrated at a volume of 10 ml/Kg bodyweight.

No. of animals per sex per dose:

five males and five females was given a single dose by gavage of the test substance, formulated in 1% acqueous methylcellulose, at a dose level of 2.0 g/Kg bodyweight.

Control animals:

no

Details on study design:

Anhydrous stannic oxide (Sn02) was prepared at a concentration of 20% w/v in 1 % w/v aqueous methylcellulose and administered at a volume of 10 mI/kg bodyweight.
The test substance was prepared on the day of dosing.
The absorption of the test substance was not determined
A group of ten rats (five males and five females) was treated at 2.0 g/kg body weight.
No control animals were included in this study.

Statistics:

no data

Sex:

male/female

Dose descriptor:

other: LD1

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths following a single oral dose of Anhydrous stannic oxide (Sn02) at 2.0 g/kg bodyweight.

Clinical signs:

other: Piloerection was observed in all rats within five minutes of dosing. This sign persisted and was accompanied at later intervals on Day 1 only by abnormal body carriage (hunched posture). Recovery of all rats, as judged by external appearance and behaviour

Gross pathology:

No macroscopic abnormalities were observed for animals killed on Day 15.

Other findings:

none

Interpretation of results:

GHS criteria not met

Conclusions:

The acute lethal oral dose to rats of Anhydrous stannic oxide (Sn02) was found to be greater than 2.0 g/kg bodyweight.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The main assumption for this read across approach is that the source substance ionic Tin (IV) and the target substance Tin (IV) dioxide NP have a common moiety (Tin ion).
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to test item sections for details.
3. ANALOGUE APPROACH JUSTIFICATION
A reliable Acute Oral Toxicity Study is available for the source substance ionic Tin (IV), showing that the substance has no acute toxicity via Oral route (The acute lethal oral dose to rats of Anhydrous stannic oxide (SnO2) was found to be greater than 2.0 g/kg bodyweight).
Since the target and the source substance dissociate to the same ion, both target and read-across substance, do share the same toxicological mechanisms and the effects of the target substance is predicted to be equal to the effects of the source substance.
The dissolving part of Tin (IV) dioxide contributes mostly to its toxicity (De Groot et al, 1973). The common compound ionic Tin (IV) is solely responsible for the absence or presence of effects.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Sex:

male/female

Dose descriptor:

other: LD1

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study in compliance with international recognized guidelines.

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

GLP compliance:

yes

Test type:

standard acute method

Species:

rat

Strain:

other: Spangue-Dawley derived, albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Number of Animals: 10
- Sex: 5 Males and 5 Females. The females assigned to test were nulliparous and non- pregnant.
- Species/Strain: Rat/Sprague-Dawley derived, albino.
- Age/Body weight: Young adult (10-11 weeks)/males 273-294 grams and females 185- 212 grams at experimental start.
- Source: Received from Harlan Laboratories, Inc. on March 14, 2012.

Enviromental conditions:
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors, which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals (Natl. Res. Council, 2011). Litter paper was placed beneath the cage and was changed at least three times per week.

- Animal Room Temperature and Relative Humidity Ranges: 20-23ºC and 46-58%, respectively.

- Animal Room Air Changes/Hour: 13. Airflow measurements are evaluated regularly and the records are kept on file at Product Safety Labs.

- Photoperiod: 12-hour light/dark cycle

- Acclimation Period: 14 days

- Food: Harlan Teklad Global 16% Protein Rodent Diet #2016 was supplied ad libitum, except during exposure.

- Water: Tap water was supplied ad libitum by an automatic water dispensing system except during exposure.

- Contaminants: There were no known contaminants reasonably expected to be found in the food or water at levels which would have interfered with the results of this study.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: water

Details on inhalation exposure:

Nose-Only Exposure Chamber: A nose-only inhalation chamber with an internal volume of approximately 28 liters (Nose-Only Inhalation Chamber, ADG Developments LTD) was used for exposure. Animals were individually housed in polycarbonate holding tu exposure. The base unit terminates the chamber with a 0.5-inch diameter tube for discharged air.

Air Supply: Approximately 30.0 liters per minute (Lpm) of filtered air was supplied by an air compressor (Powerex Model: SES05) to the spray atomization nozzle. An additional 6.0 Lpm of compressed mixing air from the air compressor was introduced into the chamber to help uniformly distribute the test atmosphere by creating a vortex at the chamber inlet. Compressed airflow was measured with a Mass Flowmeter (Omega, Model #FMA-5613). Chamber airflow was monitored throughout the exposure period and recorded periodically. Mean airflow was 36.0 Lpm. Based on the volume of the inhalation chamber, this airflow provided approximately 77 air changes per hour during the study.

Ambient Conditions: The exposure tube temperature and relative humidity ranges during exposure were 20-21ºC and 16-19%, respectively. The room temperature and relative humidity ranges during exposure were 20-21ºC and 29-30%, respectively. A humidifier was used during exposure. The measurements inside the exposure tube and the room conditions were made with a Temperature-Humidity Monitor (Fisher Scientific, 11-661-18). Temperature and relative humidity values were recorded every 15 minutes for the first hour of exposure and every 15 or 30 minutes thereafter.

Atmosphere Generation: The test atmosphere was generated using a ¼ inch JCO atomizer, (Spraying Systems Co.), FC3 fluid cap (Robert Miller Associates) and 70SS air cap (Spraying Systems Co.). Compressed generator/mixing air were supplied at 30/30 psi. The test substance was metered to the atomization nozzle through size 16 Tygon tubing, using a peristaltic pump (Master Flex, Model #7520-35).

Chamber Concentration Measurements: Gravimetric samples were withdrawn at six intervals from the breathing zone of the animals. Samples were collected using 37 mm glass fiber filters (GF/B Whatman) in a filter holder attached by ¼ inch Tygon tubing to a vacuum pump (Westech). The filter was weighed before and after collection to determine the mass collected. The collections were carried out for 1 minute at airflows of 4 Lpm. Sample airflows were measured using a Mass Flowmeter (Aalborg, Model #GFC-17).

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric analysis + flowmeter analysis

Duration of exposure:

> 4 h

Remarks on duration:

the exposure period was extended of 4 min beyond 4 hours in order to reach an equilibrium in the chamber.

Concentrations:

the dry weight gravimetric and nominal chamber concentrations were 2.04 mg/L and 236.7 mg/L, respectively. 2.4 mg/L was the highest chamber concentration achieved.

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

Prior to initiation of the full inhalation study, pre-test trials were conducted to establish generation procedures to achieve, to the extent possible, the desired chamber concentration (2.0 mg/L) and desired particle size distribution (mass median aerodynamic diameter between 1 and 4 µm).

Prior to conducting pre-test trials, attempts were made at generating the test atmosphere as a dust. However, the test substance as a powder clogged all dust generator equipment used during preliminary testing. Therefore, the unground test substance was diluted to a 25% w/w dilution in distilled water for all trials conducted. In addition, it was decided that a dry weight gravimetric measurement procedure was to be used. The exposure procedures and atomization equipment used were based on the results of pre-test trial number 2 which provided a gravimetric concentration of 2.03 mg/L with a mass median aerodynamic diameter of 2.21 µm.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.04 other: mg/L (dry weight)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: the substance was diluted in distilled water at 25% w/w

Mortality:

All animals survived exposure to the test atmosphere.

Clinical signs:

other: Following exposure four males and all five females exhibited irregular respiration. All affected rats recovered from this symptom by Day 5, and along with the fifth male, appeared active and healthy for the remainder of the observation period.

Body weight:

Individual body weights of the animals were recorded prior to test substance exposure (initial) and again on Days 1, 3, 7 and 14 (termination).
Although all rats lost body weight by Day 1 and/or through Day 3, all animals showed a weight gain over the entire study.

Gross pathology:

No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Other findings:

none

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this study, the single exposure acute inhalation LC 50 of a 25% w/w dilution of Tin dioxide in distilled water is greater than 2.04 mg/L maximum attainable (dry weight) in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

2.04 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The acute toxicity of tin dioxide was evaluated in 1 key oral (gavage) study and in a key inhalational study. The oral study was performed according to the EU Method B1 and the inhalational study according to the OECD Guideline 403. Both the studies were compliant with Good Laboratory Practices (GLP). A study was performed to assess the acute oral toxicity of anhydrous stannic oxide (SnO2) to the rat. The method followed was that described in EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC, Part B, Method B.l. Acute toxicity (oral). A group of ten fasted rats (five males and five females) was given a single dose by gavage of the test substance, formulated in 1 % w/v aqueous methylcellulose, at a dose level of 2.0 g/kg bodyweight. All animals were killed and examined macroscopically on Day 15, the end of the observation period. There were no deaths. Clinical signs of reaction to treatment were limited to piloerection and abnormal body carriage (hunched posture). Recovery was complete by Day 3. All rats achieved anticipated bodyweight gains throughout the study. No abnormalities were recorded at the macroscopic examination on Day 15. The acute lethal oral dose to rats of Anhydrous stannic oxide (SnO2) was found to be greater than 2.0 g/kg bodyweight.

An acute inhalation toxicity test was conducted with rats to determine the potential for Tin dioxide NP to produce toxicity from a single exposure via the inhalation (nose-only exposure) route. Under the conditions of this study, the single exposure acute inhalation LC 50 of a 25% w/w dilution of Tin dioxide in distilled water is greater than 2.04 mg/L maximum attainable (dry weight) in male and female rats. After establishing the desired generation procedures during the pre-test trials, ten healthy rats (5/sex) were exposed to the test atmosphere for 4 hours. Chamber concentration and particle size distributions of the test substance were determined periodically during the exposure period. The animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for 14 days following exposure. Body weights were recorded prior to exposure and again on Days 1, 3, 7 and 14 (termination). Necropsies were performed on all animals at terminal sacrifice. The dry weight gravimetric chamber concentration was 2.04 mg/L, the maximum attainable concentration. The mass median aerodynamic diameter was calculated to be 2.7 µm based on graphic analysis of the particle size distribution as measured with an ACFM Andersen Ambient Particle Sizing Sampler. All animals survived exposure to the test atmosphere. Following exposure four males and all five females exhibited irregular respiration. All affected rats recovered from this symptom by Day 5, and along with the fifth male, appeared active and healthy for the remainder of the observation period. Although all rats lost body weight by Day 1 and/or through Day 3, all animals showed a weight gain over the entire study. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Justification for selection of acute toxicity – oral endpoint
Well documented GLP study

Justification for selection of acute toxicity – inhalation endpoint
GLP study in compliance with international recognized guidelines.

Justification for classification or non-classification

The submission substance has a rat acute oral LD50 of greater than 2000 mg/kg bw. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.

The submission substance has a rat acute inhalative 4h LC50 of greater than 2.04 mg/L, the highest chamber concentration that can be obtained. There is no indication that a higher dose would result in acute toxicity. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.

No data is available to address acute dermal toxicity. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.