Germanium dioxide

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

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

Data source

Reference

Reference Type:

publication

Title:

Dose dependency of germanium-dioxide-induced nephrotoxicity in rats.

Author:

Sanai T, Onoyama K, Osato S, Motomura K, Oochi N, Oh Y, Okuda S, Takaichi S, Fujishima M.

Year:

1991

Bibliographic source:

Nephron 57(3):349-54.

Materials and methods

Principles of method if other than guideline:

In a 40 weeks pair-feeding study the dose dependency of GeO2 induced nephrotoxicity was investigated experimentally in rat groups orally treated for 24 weeks with high, moderate or low doses of GeO2 and in an untreated group.
It is not according to OECD guideline 408 for which the normal standard exposure period is of 13weeks

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Germanium dioxide

EC Number:

215-180-8

EC Name:

Germanium dioxide

Cas Number:

1310-53-8

Molecular formula:

GeO2

IUPAC Name:

Germanium dioxide

Test material form:

solid

Specific details on test material used for the study:

Source of test material: Sumitomo Metal Mining Co. Japan

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kyushu University Animal Center, Japan
- Age at study initiation: 10 weeks
- Weight at study initiation: 140-170g
- Fasting period before study:no information
- Housing: no information
- Diet (e.g. ad libitum): the amount of food administered was adjusted to the level of the group with minimal ingestion
- Water (e.g. ad libitum): no information
- Acclimation period:no information

ENVIRONMENTAL CONDITIONS
- Temperature (°C):no information
- Humidity (%):no information
- Air changes (per hr):no information
- Photoperiod (hrs dark / hrs light):no information

Administration / exposure

Route of administration:

oral: feed

Details on route of administration:

feeding study: GeO2 was mixed with powdered regular chow

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

daily

Frequency of treatment:

24 weeks

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

37.5 other: mg/kg/day

Doses / concentrations 2

Dose / conc.:

75 other: mg/kg/day

Doses / concentrations 3

Dose / conc.:

150 other: mg/kg/day

No. of animals per sex per dose:

37.5 mg/kg/day: n=4
75 mg/kg/day : n=6
150 mg/kg/day : n=5
control group: n=8

Control animals:

yes, concurrent no treatment

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no information

BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks in all the dose groups

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
In order to maintain an equal calorie and protein intake, the amount of food administered was adjusted to the level of the group with minimal ingestion

HAEMATOLOGY: Yes
hematocrit and blood urea nitrogen (BUN) were examined every 4 weeks in all the groups and also at week 10 in the high dose and control groups


URINALYSIS: Yes
24h urinary protein excretion, creatinin clearance (Ccr), serum total protein, albumin and urinalysis were examined at an early stage (weeks 5-16), an intermediate stage (weeks 17-28) and a late stage (weeks 29-40) of the experiment

Sacrifice and pathology:

HISTOPATHOLOGY: Yes

Statistics:

Data are expressed as mean +/- SD. Statistical differences were calculated using the one-way analysis of variance among groups and the unpaired t test with Bonferroni's method

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

GeO2-H group: appeared inactive and listless after week 8, 1 rats died from azotemia at week 10

Mortality:

mortality observed, treatment-related

Description (incidence):

GeO2-H group: appeared inactive and listless after week 8, 1 rats died from azotemia at week 10

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

GeO2-H: BW (93±8g): significantly lower than control group ( 185±5g) at week 10 (p<0.001); GeO2-M: BW( 103±12g): sign lower than control group (177±5g) at week 24(p<0.001); GeO2-L: BW(171.4g) sign lower than control group at week 40 (205±6) (p<0.001)

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Hematocrit: GeO2-H: 38.8±2.6%): significantly lower than control group ( 46.3±2%) at week 10 (p<0.001); GeO2-M: slightly but sign reduced at wks 12 and 16and at week 36 in GeO2-L when compared to that in the control group (p<0.05 for both groups)

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

daily urinary protein excretion did not reveal any abnormalities in any of the groups. Urinary excretion and renal tissue content of Ge were significantly elevated in the GeO2-H

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

vacuolar degeneration and depositions of granules positive for periodic acid-Schiff in distal tubules were predominant in the higher dose group of GeO2

Histopathological findings: neoplastic:

not examined

Effect levels

Dose descriptor:

LOAEL

Effect level:

37.5 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: systemic toxicity and dose dependant renal dysfunction

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:

GeO2 induced nephrotoxicity develops dose dependently

Executive summary:

In a 40-week pair-feeding study, a a dose-dependent effect of GeO2 is demonstrated in rats. This study

also demonstrated that the higher the dose the shorter the exposure duration required to develop the adverse effects. A lowest observed adverse effect dose of 37.5 mg/kg body wt/day of GeO2 or 26 mg/kg body wt/day of Ge was established for decreased growth, anemia, renal dysfunction, and renal tubular degeneration accompanied with elevated urinary and renal germanium.