Germanium tetrachloride

Endpoint summary

Description of key information

-28d repeated dose inhalation publication (Arts et al., 1994) (KL=1): 
In a guideline study, conducted to GLP, administration of rats to Germanium dioxide by inhalation 6h/d and 5d/wk for 4wk at doses of 0,16, 72, or 309 mg/m3, had adverse effects at the highest dose especially on growth, kidneys and liver. A NOAEL of 72mg/m3 was established.
- Six repeated dose oral toxicity studies were retained for a potential read across approach. 
The study reporting the most sensitive (most relevant) data point (Sanai et al., 1991) was used: LOAEL (40w) = 0.0375g/kg BW/d inducing systemic toxicity by weight loss, anemia, and hypo-proteinemia and renal dysfunction (indicated by the increase of blood urea nitrogen and the decrease of creatinine clearance). This effect concentration was converted to a LOAEL for the standard exposure period of 13weeks (0.115g/kg BW/d). 
Remark: the lowest LOAEL, which was reported by Yim et al., 1999 (0.01g/kg BW/d), was not retained for further assessment since this effect concentration was solely based on the subcellular effects mitochondrial myopathia. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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

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 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

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

Route of administration:

oral: feed

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

daily

Frequency of treatment:

40 weeks

Remarks:

Doses / Concentrations:
37.5, 75 or 150 mg/kg/day
Basis:
nominal in diet

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

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

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

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

Critical effects observed:

not specified

none

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

37.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

6 repeated dose oral toxicity studies on GeO2 are available and retained for potential read across approach but the study of Sanai et al (1991) was used since reporting the most sensitive and most relevant data point.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

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:

other: no data

Remarks on MMAD:

MMAD / GSD: dose 16 mg/m3 : MMAD: 1.2 µm, GSD: 1.9µm
dose 72mg/m3: MMAD: 1.6 µm, GSD: 1.8µm
dose 309mg/m3: MMAD: 2.0 µm, GSD: 1.7µm

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: equipment according to the ASHRAE standard
- System of generating particulates/aerosols: aerosol was generated by dispersing the test material into the air using equipment according to the ASHRAE standard. Two ASHRAE trays were used, one for generation of the high concentration, the other one for the mid concentration test atmosphere. Both trays were placed in a hood. The aerosols were subsequently diluted with clean air before entering the inhalation chamber. The low concentration test atmosphere was trapped from the inlet tube of the high concentration chamber, using an air mover and dilution before entering the low concentration chamber.
- Particle size distribution: determined with an I l-stage cascade impactor (Institute's design)
- Temperature, humidity, pressure in air chamber: 21-22 C, mean relative humidity of 42-56%, flow rate through chambers was between 17 and 34m3/hr

TEST ATMOSPHERE
- Analytical method used: The actual mass concentration of germanium dioxide in the test atmosphere was determined by gravimetry.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

none

Duration of treatment / exposure:

4 wk

Frequency of treatment:

6h/day, 5day/wk for 4 wk

Remarks:

Doses / Concentrations:
16, 72, 309 mg GeO2/m3
Basis:
nominal conc.

No. of animals per sex per dose:

5 rats of each sex per dose

Control animals:

yes, concurrent no treatment

Details on study design:

none

Positive control:

None

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
-pathology: adrenals, heart, kidneys, liver, spleen, testes, thyroid and lungs with trachea and larynx were weighed. Tissue samples of these organs and of the nose were preserved in a 4% aqueous, neutral phosphate buffered formaldehyde solution. After fixation, the noses were decalcified in nitric acid. Organs and tissues were embedded in paraffin wax. sectioned at 5 ltm and stained with haematoxylin and eosin. Kidneys were also stained with periodic acid Schiff reagent. Full microscopic examination was carried out on the adrenals, heart, spleen, thyroid, liver, kidneys, nose, lungs and trachea and larynx of all control and high concentration rats, on the kidneys of all animals of the intermediate groups, and on the kidneys and lungs of all animals of the recovery groups.
BODY WEIGHT: Yes
HAEMATOLOGY: haematological variables were measured in all fasted rats towards the end of treatment (day 23) and after a further 28 days of observation in fasted rats of the recovery groups. The variables included haemoglobin concentration, packed cell volume (haematocrit), erythrocyte and thrombocyte count, prothrombin time, and total and differential leucocyte counts.
CLINICAL CHEMISTRY: Biochemical variables were measured in rats of the main groups at the end of treatment (day 28) and in recovery rats after another 33 days of observation.
The following biochemical variables were measured in plasma obtained from heparinized blood samples at the end of the exposure period (Cobas-Bio centrifugal analyser): albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatininc, 7-glutamyltransferase, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), inorganic phosphate, potassium, sodium, total protein and urea. Fasting blood glucose was determined towards the end of treatment (day 23) and after a further 28 days of observation in rats fasted for 16 hr and deprived of water for 24 hr. Albumin, total bilirubin, creatinine, ASAT, ALAT, total protein and urea were also measured in rats of the recovery groups.
URINALYSIS: Urinalysis was carried out in all rats on day 23 and in rats of the recovery groups after another 28 days of observation. Rats were deprived
of water for 24 hr and of food during the last 16 hr of this period. Urine was collected during the last 16 hr of the deprivation period. Analyses included protein, glucose, occult blood, ketones, urobilinogen, bilirubin and pH (using test strips: Boehringer), and urinary volume and density. The sediment was also examined microscopically in pooled samples of recovery rats

Sacrifice and pathology:

pathology: adrenals, heart, kidneys, liver, spleen, testes, thyroid and lungs with trachea and larynx were weighed. Tissue samples of these organs and of the nose were preserved in a 4% aqueous, neutral phosphate buffered formaldehyde solution. After fixation, the noses were decalcified in nitric acid. Organs and tissues were embedded in paraffin wax. sectioned at 5 ltm and stained with haematoxylin and eosin. Kidneys were also stained with periodic acid Schiff reagent. Full microscopic examination was carried out on the adrenals, heart, spleen, thyroid, liver, kidneys, nose, lungs and trachea and larynx of all control and high concentration rats, on the kidneys of all animals of the intermediate groups, and on the kidneys and lungs of all animals of the recovery groups.

Statistics:

Body weight (during exposure period): one-way analysis of covariance using pre-exposure (day 0) weights as the covariate; if group means were
significantly different (P < 0.05), individual pairwise comparisons were made using Dunnett's multiple comparison tests.
Body weights (during the recovery period): two-sample t-test.
Organ weights, and haematological, urinalytical and clinicochemical data (obtained during the exposure period): analysed for each sex by one-way analysis of
variance (ANOVA). If significant differences among the means were indicated (P < 0.05), Dunnett's test was performed to determine which exposed groups
differed from the control.
Two-sample t-tests were applied to data obtained during the recovery period instead. In case of group mean differences (P < 0.05), pairwise comparisons between control and exposed groups were determined by Mann-Whitney U-tests. Mann-Whitney U-tests were applied during the recovery period instead. Incidences of histopathological changes were analysed by Fisher's exact probability test. All pairwise comparisons were two tailed. Group mean differences with an associated probability of less than 0.05 were considered to be statistically significant.

Clinical signs:

no effects observed

Description (incidence and severity):

no exposure-related changes in condition, health, behaviour or mortality

Mortality:

no mortality observed

Description (incidence):

no exposure-related changes in condition, health, behaviour or mortality

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights were significantly lower in rats of the high concentration group during almost the entire study, recovery period included

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):

decreases in haematocrit (females) and thrombocyte count (both sexes), and increases in neutrophil count (both sexes) and white blood cell count (females)

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

urinary volume was elevated, and urine density and pH were lowered in both sexes.

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Relative weights of kidneys, spleen, heart and lungs were higher than in controls.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

At the end of the treatment period , changes were observed only in rats of the high concentration group
CLINICAL SIGNS AND MORTALITY: no exposure-related changes in condition, health, behaviour or mortality

BODY WEIGHT AND WEIGHT GAIN: decreased body weight

HAEMATOLOGY: decreases in haematocrit (females) and thrombocyte count (both sexes), and increases in neutrophil count (both sexes) and white blood cell count (females)

CLINICAL CHEMISTRY: decreased fasting blood glucose (females), decreased total protein concentration (both sexes),
increased plasma alanine aminotransferase and aspartate aminotransferase activities (females). increased plasma urea nitrogen (males) and increased plasma bilirubin level (females) were observed

URINALYSIS: urinary volume was elevated, and urine density and pH were lowered in both sexes.

ORGAN WEIGHTS: Relative weights of kidneys, spleen, heart and lungs were higher than in controls.

HISTOPATHOLOGY: NON-NEOPLASTIC: Microscopical examination revealed treatment-related changes in the kidneys, consisting of an increased occurrence of proximal as well as distal basophilic tubules in high concentration rats of both sexes, in addition, tubules with hypertrophic
epithelial cells were observed. Increased occurrence of proximal basophilic and tubules with hypertrophic cells concomitant with distal tubular and collecting tubular vacuolation of epithelial cells was still present in the tubular cells of exposed rats at the end of the recovery period. PAS-positive granules were present both at the end of treatment at 309 mg/m3 and after recovery; the granules were larger at the end of the recovery period than just after treatment. No treatment-related histopathological changes were observed in the adrenals, heart, nasal cavity, larynx, trachea, lungs, liver, spleen and thyroid.

Dose descriptor:

NOAEL

Effect level:

72 mg/m³ air

Sex:

male/female

Basis for effect level:

other: effects on growth rate, kidney

Dose descriptor:

LOAEL

Effect level:

309 mg/m³ air

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

none

Conclusions:

Considering the observed effects on growth, kidneys and liver in rats exposed to 309 mg/m3, it is concluded that the no-toxic-effect level in the present study is 72 mg/m3

Executive summary:

A study was conducted to determine the effects of sub-acute exposure of the test material on the respiratory system in Wistar rats.

The test material was administered by inhalation 6 h /d and 5 d/wk for 4wk at 0, 16, 72, or 309 mg/m3 to groups of 5 rats/sex/dose. Two additional groups of 5 rats per sex, exposed either to 0 or to 309 mg/m3. were kept for a 33,.day post-exposure period. At the end of the treatment period, changes were observed only in rats of the high concentration group: these changes were decreased body weight gain (both sexes), decreases in haematocrit (females) and thrombocyte count (both sexes), and increases in neutrophil count (both sexes) and white blood cell count (females). On clinical chemistry evaluation, decreased fasting blood glucose (females), decreased total protein concentration (both sexes), increased plasma alanine aminotransferase and aspartate aminotransferase activities (females). increased plasma urea nitrogen (males) and increased plasma bilirubin level (females) were observed. In addition, urinary volume was elevated, and urine density and pH were lowered in both sexes. Relative weights of kidneys, spleen, heart and lungs were higher than in controls. Microscopic examination revealed effects on renal tubular epithelium. Effects on growth, kidneys, and liver were still present at the end of the 33-day recovery period.

It was concluded that the no-adverse-effect-level in the 4-wk study using hexagonal germanium dioxide was 72 mg/m3.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

72 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The study is GLP compliant and of high quality (klimisch score=1). The other available studies are Klimisch score=4

Additional information

GeCl₄is a data-poor substance. However, a relatively large amount of toxicity data is available for GeO₂. Since GeCl₄readily hydrolyses (even with the humidity in the air) to form GeO₂and HCl, the applicability of using GeO₂toxicity data to read across to GeCl₄was evaluated.

In order to make a straightforward comparison possible between available data on GeCl4 and GeO2,the effect concentrations reported for GeCl₄were converted to their GeO₂equivalents (i. e. effects concentrations are corrected for molecular weight). 

Repeated dose toxicity: inhalation:

A chemical is classified as a STOT RE (inhalation) cat 2 if the effect concentration < 600mg/m³ (for a 28-day toxicity study). Based on the repeated dose inhalation study (Arts et al., 1994), GeO₂can be categorized as a STOT RE cat 2. However, this discussion on STOT RE classification is not relevant for GeCl₄since the LOAEL given for GeO₂, is too close to the acute lethal effect concentrations of GeCl4 (Terrill et al., 1990) expressed as normalized equivalents of GeO2 (see table below). This implies that the animals will have died before any STOT effect would be able to occur.

Repeated dose toxicity: oral:

A compound is considered to be a STOT RE (oral) cat 2 if 10 < effect conc < 100mg/kg BW/d. However these references values refer to effects seen in a standard 90-day toxicity study. Similar to Haber’s rule for inhalation (effective dose is directly proportional to exposure concentration and the duration of exposure), the LOAEL (Sanai et al., 1991) based on 40w experiment was converted to the 13w standard (LOAEL = 115mg/kg BW/d), resulting in no STOT RE classification. Remark: the lowest LOAEL, which was reported by Yim et al., 1999 (0.01g/kg BW/d), was not retained for further assessment since this effect concentration was solely based on the subcellular effects mitochondrial myopathia.

This discussion on classification, however, is not relevant for GeCl₄, since the LOAEL of GeO₂is higher than the extrapolated acute lethal concentration (expressed as normalized equivalent GeO₂-see table below).

Table: Overview of available acute toxicity data on GeCl4 and GeO2 and overview of the conversion of GeCl4 effect data to GeO2 equivalents(based on molecular weight).

* route to route extrapolation: 3,316mg/L x 0,8L/min/kg x 60min ==> LD100 = 159mg/kg (allometric scaling principle - Echa guidance R8); **Classification/effects not relevant for GeCl4: LOAEL too close to acute lethal conc; *** Classification/effects not relevant for GeCl4: LOAEL >acute lethal conc

	Reference	Klimisch	Exposure range			Duration	Effectconc	Qualifier	Normalization to equivalent GeO2 Exposure range         Effect
GeCl4	acute inhal (Terrill et al., 1990, Hazleton laboratories)	2	3.316	/	g/m3	1h	3.316g/m3	EC100	1.632           /	1.632g/m3
	data extrapolated to 4h standard					4h	0.829g/m3	EC100		0.408g/m3
	route-to-route extrapolation*						0.159g/kg	ED100		0.078g/kg
GeO2	acute inhal (Arts et al., 1994)	2	3.1	/	g/m3	4h	>3.1g/m3	LC50	lethal conc GeO2 > GeCl4 lethal conc GeO2 > GeCl4 lethal conc GeO2 > GeCl4     STOT RE 2 **      no STOT RE class ***
			1.42	/	g/m3	4h	>1.42g/m3	LC50
	acute oral (Faroon et al., 2007)	3	/	/	g/kg	NI	3.7g/kg	LD50
	acute oral (Faroon et al. , 2007)	3	/	/	g/kg	NI	6.3g/kg	LD50
	repeated dose - inhal (Arts et al., 1994)	1	0.016	0.309	g/m3/d	6h/d ; 4w	0.072g/m3/d 0.309g/m3/d	NOAEL LOAEL
	repeated dose - oral (Sanai et al., 1991)	2	0.0375	0.15	g/kg/d	40w	0.0375g/kg/d	LOAEL
	data extrapolated to 13w (90d) standard					13w	0.1154g/kg/d	LOAEL
	repeated dose - oral (Higuchi et al., 1989)	2	0.1	0.15	g/kg/d	4m	0.1g/kg/d	LOAEL
	repeated dose - oral (Higuchi et al., 1991)	2	/	0.1	g/kg/d	up to 8m	0.1g/kg/d	LOAEL
	repeated dose - oral (Nakano., 1987)	3	0.1	0.5	g/kg/d	9m	0.1 g/kg/d	LOAEL
	repeated dose - oral (Yim et al., 1999)	2	0.005	0.15	g/kg/d	4,8,16,24w	0.01 g/kg/d	LOAEL
	repeated dose - oral (Matsumuro et al., 1993)	2	/	0.1	g/kg/d	up to 8m	0.1g/kg/d	LOAEL

Valid to read across based on GeO₂data?

Based on this exercise it was envisaged to evaluate whether a read across from GeO₂-induced systemic effects would be valid for GeCl_4.The answer to this question is clearly negative. Corrosive effects of GeCl₄ (attributable to hydrolysis with formation of HCl ) will occur at much lower concentration and before other potential GeO₂-induced effects can be induced.

Because of the high corrosive potential of GeCl₄at relatively low concentrations, it was concluded that read across based of GeO₂toxicity data is not relevant: Severe corrosive effects of GeCl₄will occur before systemic effects triggered by GeO₂can be initiated.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
study reporting the most sensitive and most relevant data point and klimisch score 2

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
only one study availabe which is klimisch score=1

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Repeated dose toxicity: inhalation:

A chemical is classified as a STOT RE (inhalation) cat 2 if the effect concentration < 600mg/m³ (for a 28-day toxicity study). Based on the repeated dose inhalation study (Arts et al., 1994), GeO₂ can be categorized as a STOT RE cat 2. This discussion, however, on STOT RE classification is not relevant for GeCl₄ since the LOAEL given for GeO₂, is too close to the acute lethal effect concentrations (i.e. animals will have died before any STOT effect would be able to occur).

Repeated dose toxicity: oral:

A compound is considered to be a STOT RE (oral) cat 2 if 10 < effect conc < 100mg/kg BW/d. However these references values refer to effects seen in a standard 90-day toxicity study. Similar to Haber’s rule for inhalation (effective dose is directly proportional to exposure concentration and the duration of exposure), the LOAEL (Sanai et al., 1991) based on 40w experiment was converted to the 13w standard (LOAEL = 115mg/kg BW/d), resulting in no STOT RE classification. However, this discussion on classification is not relevant for GeCl₄, since the LOAEL of GeO₂is higher than the acute lethal concentration (normalized equivalent GeO₂).