Germanium dioxide

Endpoint summary

Description of key information

Assessment of the acute oral toxicity of germanium dioxide in Arulnesan et al 2012:

An Acute Oral Toxicity Study of Germanium Dioxide, was carried out according to OECD 425. The test item was suspended in 1% methyl cellulose at a concentration of 200 mg/mL. The first animal was dosed at 2000 mg/kg at a dose volume of 10.0 mL/kg. Since this first animal survived, four additional animals were dosed at 2-day intervals. A total of 5 female CD (Sprague-Dawley) rats were dosed. All animals received the test item by oral gavage using a feeding cannula inserted into the stomach of the animals. The animals were observed for a 14-day period after dosing. Body weights were recorded prior to test item administration (i.e., Day 0), on Day 7 and prior to necropsy on Day 14. No mortalities were observed post dosing and during the 14-day observation period in any of the animals. All rats gained body weight by Day 7 and at the end of the study. At the end of the 14-day observation period, each animal was sacrificed and submitted for gross necropsy. No gross pathological findings were observed in any of the rats at necropsy. Based on the foregoing results, the acute oral LD50 in rats of the test item, Germanium Dioxide, was found to be in excess of 2000 mg/kg. Therefore, the test item is considered not to present a significant acute toxic risk if swallowed.

Assessment of the acute inhalation toxicity of germanium dioxide in Arts et al 1994:

The acute (4 -hour) inhalation toxicity of amorphous and hexagonal germanium dioxide was studied by exposing total-body one group of rats, consisting of five male and five female rats, to a test atmosphere containing amorphous germanium dioxide and hexagonal germanium dioxide at maximum attainable concentrations of 3.10 and 1.42 g/m3 in air respectively for one single time for a period of 4 hours.

It was concluded that the 4 hours LC50 value of amorphous germanium dioxide was higher than 3.10g/m3 and that the 4 hours LC50 value of hexagonal germanium dioxide was higher than 1.42g/m3.

In addition, a dustiness test on dust fractions of 1g GeO2 is performed.  It can be concluded from this dustiness test that the tested sample is showing little dustiness with very small dustiness values for the alveolar fraction.  Therefore, it can be concluded that the LC 50 > 3.10 g/m3 and > 1.42 g/m3 (maximum attainable concentration) implicates LC 50 > 5 g/m3 indicating GHS criteria not met for classification (reference: Final - Report on the determination of the dust generation tendency (“dustiness”) of germanium dioxide -  Report no. APS 2 00 007, 2017, DMT GmbH & Co. KG  

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Canada, Montreal, Quebec
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Approximately 10 to 11 weeks
- Weight at study initiation: 225.7 - 238.1 g after fasting. The weight variation in animals at the start of the study did not exceed ± 20 percent of the mean weight
- Fasting period before study: yes
- Housing: Female rats were individually housed in separate quarters in solid bottom cages. Individual animals were identified by colour coding, the animal number and group number also appeared on the outside of each cage to preclude mix-up.
The cage cleaning schedule, air filtration and recirculation, health checks and facility maintenance were carried out in accordance with the applicable Nucro-Technics’ Standard Operating Procedures, and such activities were recorded in the animal room
records.
Animals were housed and maintained according to the AAALAC International Guide for the Care and Use of Laboratory Animals, CCAC Guidelines for Care and Use of Experimental Animals and Nucro-Technics’ Standard Operating Procedures.
Animal Selection:
The test population of animals was selected from newly arrived, previously unused rats.
- Diet/ Water: Teklad Certified Rodent Diet and water were offered ad libitum throughout the acclimatization and study periods. All animals used for the Limit Test were fasted over-night. Food but not water was withheld from 4:00 to 4:30 p.m. on the day preceding dosing. Food was returned to the cages approximately 1 hour after dosing.
- Acclimation period:10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19°C to 25°C
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

1%

Details on oral exposure:

VEHICLE
- Concentration in vehicle: suspended in 1% methyl cellulose to obtain a concentration of 200.0 mg/mL of test item


MAXIMUM DOSE VOLUME APPLIED: The animals were dosed at 2000 mg/kg (10.0 mL/kg by volume of test item preparation). The individual doses of the test item preparation were individually calculated for each animal based on the body weight of the
animal.


PROCEDURE:
The chemical composition indicated that the test item was likely to be non-toxic, therefore, a decision was made to proceed with the Limit Test. The first animal was dosed at 2000 mg/kg. Since this animal survived, four additional animals were sequentially dosed at 2-day intervals. A total of five animals were tested.

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were individually observed once during the first 30 minutes after dosing and periodically during the first 24 hours following dosing (with special attention given during the first 4 hours). Observations once daily were carried out for the remainder of the study. The animals were observed for 14 days after the dosing. Cageside observations were directed towards any changes in the skin and fur; eyes and mucous membranes; respiratory, circulatory, autonomic and central nervous system; and also somatomotor activity and behaviour pattern. Particular attention was directed to any observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and/or coma. All observations were recorded daily for the entire study period using the In-Life Module V.6.1, and the entries were monitored by the Study Director. The body weights of the animals were determined prior to test item administration (i.e., Day 0), on Day 7 and on Day 14. Body weight gains were calculated.
- Necropsy of survivors performed: yes: Gross necropsy was performed on each rat at the end of the 14-day observation period and necropsy included an examination of: external surfaces of the body; all orifices; cranial cavity; external surfaces of the brain and spinal cord; nasal cavity and paranasal sinuses; thoracic, abdominal, and pelvic cavities and viscera.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Statistics:

For calculation of LD50, results were entered into the Acute Oral Toxicity statistical program, V.1.0.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities were observed post dosing and during the 14-day observation period in any of the animals.

Clinical signs:

other: no specific abnormal clinical signs

Gross pathology:

No gross pathological findings were observed in any of the rats at necropsy.

Mean group body weights are presented in Table 1.

Table 1: Body Weight Summary

Mean Group Body Weight (g) ± S.D. (g); n = 5
initial	day 7	day 14	Mean Group Body Weight Gain (g) ± S.D. (g); n = 5
232.1 ± 4.8	249.4 ± 10.7	264.8 ± 11.9	32.7 ± 10.1

Interpretation of results:

GHS criteria not met

Conclusions:

the acute oral LD50 in rats of the test item, Germanium Dioxide, was found to be in excess of 2000 mg/kg. Therefore, the test item is considered not to present a significant acute toxic risk if swallowed.

Executive summary:

An Acute Oral Toxicity Study of the test item, Germanium Dioxide, was carried out at Nucro-Technics according to Study Plan No. CNR/253801. The test item was suspended in 1% methyl cellulose at a concentration of 200 mg/mL. The first animal was dosed at 2000 mg/kg at a dose volume of 10.0 mL/kg. Since this first animal survived, four additional animals were dosed at 2-day intervals. A total of 5 female CD (Sprague-Dawley) rats were dosed. All animals received the test item by oral gavage using a feeding cannula inserted into the stomach of the animals. The animals were observed for a 14-day period after dosing. Body weights were recorded prior to test item administration (i.e., Day 0), on Day 7 and prior to necropsy on Day 14. No mortalities were observed post dosing and during the 14-day observation period in any of the animals. All rats gained body weight by Day 7 and at the end of the study. At the end of the 14-day observation period, each animal was sacrificed and submitted for gross necropsy. No gross pathological findings were observed in any of the rats at necropsy. Based on the foregoing results, the acute oral LD50 in rats of the test item, Germanium Dioxide, was found to be in excess of 2000 mg/kg. Therefore, the test item is considered not to present a significant acute toxic risk if swallowed.

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:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan CPB (Austerlitz, the Netherlands)
- Age at study initiation: 10 weeks
- Weight at study initiation: mean body weight: M: 197g, F: 138g
- Housing: individually in wire-mesh stainless steel cages
- Diet : cereal based Institute's stock diet ad libitum
- Water : ad libitum
- Acclimation period: acclimatized to the laboratory conditions in the inhalation facilities until the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

not specified

Mass median aerodynamic diameter (MMAD):

ca. 1.7 - ca. 2 µm

Geometric standard deviation (GSD):

ca. 1.5 - ca. 1.6

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION:
The hexagonal/ amorphous germanium dioxide test atmosphere was generated by continuously delivering controlled quantities of the test material by an AccuRate dry material feeder to an air driven jet mill. A vibration apparatus was placed at the outlet of the AccuRate feeder in order to
prevent compaction of the test material. The resulting aerosol was mixed with the supply air and transported to the inlet of the exposure chamber.
TEST ATMOSPHERE
The actual concentration of hexagonal/amorphous germanium dioxide in the test atmosphere was determined at least two times each hour by gravimetry. Measured test atmosphere samples were drawn through fiber glass filters (Sartorius 13430-44-S). The weights of the deposits on the filters were obtained by weighing the filters before and after sampling using a microbalance (Mettler AE163). The nominal concentration was determined by
dividing the amount used per hour by the AccuRate feeder by the total volume of air passed through the inhalation chamber.
The particle size distribution of the test material was determined once in a sample taken from the test atmosphere in the chamber using an 11-stage
cascade impactor.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

3.10g/m3 (amorphous GeO2); 1.42g/m3 (hexagonal)

No. of animals per sex per dose:

one group of 5 rats per sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 3 times (prior to exposure, at days 7 and days 14)
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight,histopathology

Statistics:

no statistics reported

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 3 100 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: amorphous

Remarks:

3100 mg/m3 is the maximum attainable concentration

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1 420 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: hexagonal

Remarks:

1420 mg/m3 is the maximum attainable concentration

Mortality:

none of the rats died

Clinical signs:

other: Rats were restless at the start of exposure (hexagonal grade) or during the entire exposure period (amorphous grade). Swallowing was observed soon after the start of exposure (amorphous). Piloerection started about 30-40min after the start of exposure an

Body weight:

body weights were reduced 7 days after exposure to amorphous GeO2; body weights were generally unaffected by exposure to the hexagonal grade

Gross pathology:

greyish and spotted lungs after exposure to hexagonal GeO2
microscopic examination: (multi)focal accumulation of alveolar macrophages was observed in almost all rats, whereas (multi)focal increased septal cellularity was observed in 30-50% of the rats. One male rat exposed to amorphous GeO2 showed multifocal alveolar bronchiolization; focal pneumonitis was observed in 2 male rats exposed to hexagonal GeO2

Other findings:

none

none

Interpretation of results:

other: study combined with Dustiness test indicates GHS criteria are not met for classification

Remarks:

The non-classification for acute toxicity by inhalation route, is supported by a dustiness test on dust fractions of 1g GeO2. It can be concluded from this dustiness test that the tested sample is showing little dustiness with very small dustiness values for the alveolar fraction. Therefore it can be concluded that the LC 50 > 3.10 g/m3 ir > 1.42 g/m3 (maximum attainable concentration) implicates LC 50 > 5 g/m3 indicating GHS criteria not met for classificaiton (reference: Final - Report on the determination of the dust generation tendency (“dustiness”) of germanium dioxide - Report no. APS 2 00 007, 2017, DMT GmbH & Co. KG

Conclusions:

4 hours LC50 value of amorphous germanium dioxide was higher than 3.10g/m3
4 hours LC50 value of hexagonal germanium dioxide was higher than 1.42g/m3

Executive summary:

The acute (4 -hour) inhalation toxicity of amorphous and hexagonal germanium dioxide was studied by exposing total-body one group of rats, consisting of five male and five female rats , to a test atmosphere containing amorphous germanium dioxide and hegonal germanium dioxide at a concentration of 3.10 and 1.42 g/m3 in air respectively for one single time for a period of 4 hours.

It was concluded that the 4 hours LC50 value of amorphous germanium dioxide was higher than 3.10g/m3 and that the 4 hours LC50 value of hexagonal germanium dioxide was higher than 1.42g/m3

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the results of the available acute oral rat study, germanium dioxide does not require classification for acute oral toxicity according to EU CLP criteria (EC 1272/2008).

Based on the results of the available acute inhalation rat study and additional dustiness testing, germanium dioxide does not require classification for acute inhalation toxicity according to EU CLP criteria (EC 1272/2008).

It was concluded that the 4 hours LC50 value of amorphous germanium dioxide was higher than 3.10g/m3 and that the 4 hours LC50 value of hexagonal germanium dioxide was higher than 1.42g/m3.

In addition, a dustiness test on dust fractions of 1g GeO2 is performed.  It can be concluded from this dustiness test that the tested sample is showing little dustiness with very small dustiness values for the alveolar fraction.  Therefore, it can be concluded that the LC50 > 3.10 g/m3 and > 1.42 g/m3 (maximum attainable concentration) implicates LC50 > 5 g/m3 indicating GHS criteria not met for classificaiton (reference: Final - Report on the determination of the dust generation tendency (“dustiness”) of germanium dioxide -  Report no. APS 2 00 007, 2017, DMT GmbH & Co. KG  

There are no available data on which to evaluate acute dermal toxicity. However, acute dermal toxicity can be considered low in view of the poor absorption by this route and the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route. Therefore, germanium dioxide does not require classification for acute dermal toxicity according to EU CLP criteria (EC 1272/2008)

No clear evidence of specific target organ toxicity was noted. As such, classification for STOT-SE is not considered appropriate.