GASIR1

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

The quality of the test atmosphere fully complied with criteria documented in the respective guidelines: OECD 403, EPA OPPTS 870.1300 and Council Regulation (EC) No 440/2008.

Deviations:

yes

Remarks:

The temperature in the animal room was slightly increased (up to 0.7°C higher than the upper limit) on two days during the acclimation period. This deviation was considered to have no impact on the outcome of the study and interpretation of the results.

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Details on test material:

- Name of test material (as cited in study report): GASIR1
- Substance type:active substance
- Physical state:red-brown powder
- Analytical purity:100%
- Composition of test material, percentage of components:Germanium 22%, Arsenicum 20%, Selenium 58%
- Purity test date:01/07/2011
- Lot/batch No.:3034-2
- Expiration date of the lot/batch:30/06/2013
- Stability under test conditions: OK
- Storage condition of test material:room temperature (15-30°C), under inert gas
- Other:

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Charles River Laboratories, Research Model and Services, Germany GmbH (Sandhofer Weg 7, D-97633, Sulzfeld)
- Age at study initiation: 8-9 weeks old (sighting exposure), 9-10 weeks old (main study)
- Weight at study initiation: male: 344g, female: 214g (sighting exposure), male: 360-394g, female: 222-244g (main study)
- Housing: Group caging (5 animals, by sex, per cage), during the sighting study individual caging
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:6 days (sighting study) or 8 days (main study)

ENVIRONMENTAL CONDITIONS
- Temperature (°C):19.5-25.7°C
- Humidity (%):40-70%
- Air changes (per hr):15
- Photoperiod (hrs dark / hrs light): 12hrs dark/12hrs light

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:TSE Rodent Exposure System (TSE Systems GmbH, Bad Homburg, Germany).
- Exposure chamber volume: 3.85L
- Method of holding animals in test chamber: polycarbonate restraint tubes
- Source and rate of air: 0.5L/min
- Method of conditioning air:
- System of generating particulates/aerosols: Rotating brush dust generator Palas RBG 1000 (Palas GmbH, Karlsruhe, Germany)
- Method of particle size determination: From the animal breathing zone using a cascade impactor
- Treatment of exhaust air: through a suitable filter system
- Temperature: 27.5°C, humidity: 9.6%, pressure in air chamber: no data

TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere was sampled at regular intervals during the exposure period. Samples were taken from an unoccupied exposure port (representing the animal's breathing zone) by pulling a suitable volume of test atmosphere through weighed GF10 glass fibre filters (Whatman, Germany, ref. no. 10370302). The difference in the pre and post sampling weights, divided by the volume of atmosphere sampled, was equal to the actual achieved test atmosphere concentration.
- Samples taken from breathing zone: yes. Filter samples were collected at the breathing zone (approx. every 10-20 minutes) during each 4-hour exposure period and analyzed.

VEHICLE
- Composition of vehicle (if applicable):
- Concentration of test material in vehicle (if applicable):
- Justification of choice of vehicle:
- Lot/batch no. (if required):
- Purity:

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The particle size of the test atmosphere was determined three times during the exposure period using a 7-stage impactor of Mercer style (TSE systems GmbH, Bad Homburg, Germany).
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.53µm (MMAD), 2.38 (GSD) (=sighting group); 2.41µm (MMAD), 2.32 (GSD) (=main study).

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5.04mg/l

No. of animals per sex per dose:

1 male/female (sighting exposure)
5 male/female (main study)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Morbidity/mortality: 1 hour after exposure and twice daily during the 14-day observation period. Clinical signs: hourly intervals during exposure and twice a day the day of exposure and once daily for 14 days. Bodyweight: on day 1, 3, 7, 14.
- Necropsy of survivors performed: yes

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.04 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No animals died during the study.

Clinical signs:

other: In group 0.1 (sighting exposure): slightly to moderate laboured respiration was recorded up to 1 hour after exposure. In group 1 (main study): slight laboured respiration was observed in all animals during the exposure and shortly thereafter when removed

Body weight:

In Group 0.1 as sighting group, slight body weight loss was observed in the male animal. The body weight returned to the initial values on Day 3.
In Group 1, slight body weight loss (1-8%) was observed in all animals, except two female rats (no.: 8236, 8239) where moderate body weight loss (11-12%) was recorded. The body weight of 4 males (no.: 8207, 8210, 8211, 8212) and one female (no.: 8242) returned to the initial values on approximately on Day 3, while a single male (no.: 8209) and 4 female animals (no.: 8236, 8239, 8240, 8241) gained their initial body weight back on approximately Day 7.

Gross pathology:

There was no evidence of any macroscopic observations at a concentration of 5.04 mg/l in animals terminated on day 14.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the experimental conditions of this study, no lethality occurred in Group 0.1 or Group 1 when exposed to an aerosol concentration of 5.04 mg/L each for 4 hours. The acute inhalation median lethal concentration (LC50) of GASIR1 in Wistar Crl:WI rats was therefore considered to be above 5.04 mg/L.

Executive summary:

1.1. STUDY DESIGN

Wistar Crl:WI rats were exposed to a test atmosphere of GASIR1 at concentration of 5.04 mg/L. The test item was administered as supplied by the Sponsor without any preparation.

The study was performed in two steps. A sighting exposure was performed first, where test atmospheres at concentrations of 5.04 mg/L was tested on single animals of both sexes. No lethality was observed at this concentration. Thereafter the main study was performed at a concentration of 5.04 mg/L. Five male and five female rats were used in the main group (Group 1). In both study phases, the animals were exposed to the test atmosphere for 4 hours using a nose-only exposure system. Aerosol concentration was measured gravimetrically 18 times during each 4-hour exposure in both parts of the study and the particle size distribution of the test aerosol was determined 3 times. The day of exposure was designated Day 0 in both parts of the study and a 14-day observation period followed the exposures.

Clinical observations were performed for all animals during exposure at hourly intervals, following removal from restraint, approximately 1hour following the end of the exposure, and daily for 14 days thereafter. Body weight was measured on Days 0 (before the exposure), 1, 3, 7 and 14. Gross necropsy was performed on the animal that died and on all animals sacrificed on Day 14.

No control group was exposed in this study.

1.2. RESULTS

The quality of the test atmosphere fully complied with criteria documented in the respective guidelines: OECD 403, EPA OPPTS 870.1300 and Council Regulation (EC) No 440/2008.

The mean achieved atmosphere concentration in the study was 5.04 mg/L in both Group 0.1 and Group 1. The mass median aerodynamic diameter (MMAD) was 2.53 μm and 2.41μm with geometric standard deviation (GSD) 2.38 and 2.32 in the Sighting Group and the Main Group, respectively.

Sighting Exposure

Initially, a single male and female rats (Group 0.1) were exposed to the aerosol concentration of 5.04 mg/L. Both animals survived.

The main clinical sign was laboured respiration, slight in the male rat and slight to moderate in the female animal. A slight body weight loss was also observed on Days 0-3 in the male of Group 0.1. The body weight returned to the initial value on Day 3.

At the necropsy, no external or internal finding was recorded in Group 0.1.

Main Study

Mortality

No mortality was noted in Group 1, either during the exposure or during the 14 day observation period.

Clinical findings

In Group 1, slight laboured respiration was observed in all animals during the exposure and shortly thereafter when removed from the restraint tubes. Increased respiratory rate (slight) was also recorded in 3 out of 5 males and in 2 out of 5 females on Day 0. Slightly weak body condition was noted in 2/5 males and 4/5 females and persisted for up to Day 2 in males and up to Day 6 in females. In a single female, moderately weak body condition was observed on Day 1 and Day 2. From Day 7 all animals were symptom-free.

Additionally, fur stained by test item was commonly observed in all animals following the exposure and persisting for up to Day 5. Wet fur was also generally recorded in all animals on the day of exposure. This observation was considered to be related to the restraint and exposure procedures and was considered not to be toxicologically significant.

Body weight

In Group 1, slight body weight loss (1-8%) was observed in all animals, except two female rats where moderate body weight loss (11-12%) was recorded. The body weight of 4 males and one female returned to the initial values on approximately on Day 3, while a single male and 4 female animals gained their initial body weight back on approximately Day 7.

Necropsy

No external or internal finding was recorded at necropsy in Group 1.

1.3. CONCLUSION

Under the experimental conditions of this study, no lethality occurred in Group 0.1 or Group 1 when exposed to an aerosol concentration of 5.04 mg/L each for 4 hours. The acute inhalation median lethal concentration (LC50) of GASIR1 in Wistar Crl:WI rats was therefore considered to be above 5.04 mg/L.