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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
335 µg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEC
Modified dose descriptor starting point:
NOAEC
Value:
335 µg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.24 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
LOAEL
Modified dose descriptor starting point:
NOAEL
Value:
0.24 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
exposure duration is chronic
AF for interspecies differences (allometric scaling):
4
Justification:
allometric scaling rat-human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - workers

Derivation of inhalation DNEL (systemic effects, long term, inhalation route)

Kidney systemic effects are the most critical and used as starting point for the derivation of inhalation DNEL, systemic effects, long term for the workers. The NOAEC of the study Arts et al 1994 is used for the DNEL derivation.

Kidney damage was observed in the 28d inhalation study in which rats were exposed to germanium dioxide (Arts et al., 1994). At 309 mg / m³ basophilic tubules as well as hypertrophy of tubular epithelial cells with vacuole formation occurred. These effects were still detectable at the end of an exposure-free follow-up period. The NOAEC for nephrotoxic effects in this study was 72 mg GeO2 / m³ (corresponding to 50 mg Ge / m³).

 

In the study on elemental germanium (Arts et al., 1990) slight changes in blood plasma creatinine and decreased specific urinary density were observed at 65.1 mg / m³. Due to the lack of dose dependence (comparison with follow-up control group), the significant change in only one sex and lack of other evidence of nephrotoxicity, the study is not suitable for the designation of a "point of departure".

 

This results in a certain discrepancy in the NOAEC between the study with germanium powder and germanium dioxide (NOAEC> 65 mg / m³ vs. 50 mg / m³). Since the particle diameter in the study with germanium dioxide was rather smaller than in the study with germanium powder (MMD with germanium powder 1.8-2.4 μm, MMAD with germanium dioxide 1.2-2.0 μm), the different potency is probably not due conditional on this parameter. The difference could be due to different solubility. Since a common DNEL is preferably to be used for germanium dioxide as well as for elemental germanium (in terms of protection of workers), the lower NOAEC is used in the following as a possible basis for the corresponding derivation.

 

NOAEC = 72 mg GeO2/m3 = 50 mg Ge/m3

NOAEC= 50 mg Ge/m3

Corrected NOAEC= inhalatory NOAEC x exp cond rat/exp cond human

                                = 50 mg/m3 x 6h/d/8h/d x 6.7m3 (8h)/10m3 (8h)

                                =25.125 mg Ge/m3

 

DNEL derivation and applying AF

 

 

 

Value

Comment

Starting point

25.125 mg Ge/m3

 

Corrected NOAEC from an inhalation 28 days study in rats (Arts et al 1994)

Assessment factor

/*

Interspecies difference, allometric scaling rat - human

2.5

Interspecies difference - remaining  differences

5

Intraspecies variation, workers

6

Exposure duration (subacute to chronic)

1

Dose-response

1

Quality of whole database

DNEL

335 µg Ge/m3

 

 

*allometric scaling is usually not applied in the derivation of the inhalation DNEL. In that case, differences in the allometry are assumed to be compensated by differences in the respiration rate. (ECHA practical Guide 14, 2012). Allometric scaling in order to adjust for physiologically-based species differences is widely accepted for systemic toxicity after oral or dermal administration. However, it does not apply to local or systemic effects after inhalation because the inhalation rate in humans is 4-fold lower compared to rats according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account (ECETOC 2010 TR No.110). 

Derivation of dermal DNEL (systemic effects, long term, dermal route)

Oral systemic data is used as starting point for derivation of Dermal DNEL by route to route extrapolation:

The study of Sanai et al (1991) (repeated dose toxicity, oral) is used as starting point for derivation of dermal DNEL, systemic effects, long term for the workers.

In a 40-week pair-feeding study (24 wks exposure with follow-up up to 40 weeks), 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.

The LOAEL was 26 mg/kg/bw day. No NOAEL could be determined (see section 5.6.1. repeated dose toxicity: oral). To convert a LOAEL to a NOAEL, the REACH TGD (Chapter R.8 of the ‘Guidance on information requirements and chemical safety assessment’) suggests an assessment factor (AF) of 3 as minimum for the majority of cases and going up to a default of 10 for exceptional cases. An AF of 3 is applied to convert LOAEL to NOAEL

 

LOAEL= 26 mg/kg/bw day

NOAEL = 26/3= 8.6 mg/kg/bw/day

 

For the dermal systemic DNEL: (route to route extrapolation: oral to dermal):

Dermal NOAEL= oral NOAEL * (exp cond rat/exp cond human workers)* (ABS oral rat/ABS dermal rat) * ABS dermal rat/ABS dermal human

= 8.6 mg/kg/bw day * (7days/5days) * 1/1

= 12 mg/kg/bw day

DNEL derivation and applying AF

 

Value

Comment

Starting point

12mg/kgbw/ day

 

NOAEL from an oral 24 weeks repeated dose tox study in rats (Sanai et al 1991) converted to corrected dermal NOAEL

Assessment factor

4

Interspecies difference, allometric scaling rat - human

2.5

Interspecies difference - remaining  differences

5

Intraspecies variation, workers

1

Exposure duration (chronic)

1

Dose-response

1

Quality of whole database

DNEL

0.24 mg Ge/kgbw/day

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Manufacturing sites of germanium are tightly controlled in their emissions

Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population