Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
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:
no hazard identified
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:
no hazard identified

Additional information - workers

Assessment factors

Assessment factors were chosen based on the respective ECHA Guidance on CSA (except for duration of exposure extrapolation and interspecies differences, see below).

Rationale for deviation from standard factors as given in ECHA Guidance on CSA

a) Duration of exposure

The default assessment factor given in ECHA Guidance on CSA for extrapolation of exposure duration from sub-acute exposure to chronic exposure is 6. However, according to Guidance given in ECETOC Technical Report 86 (2003) "No additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity", because it is believed that the threshold for cytotoxicity is the similar between species (sources cited in ECETOC Technical Report 86 (2003)).

In both repeated dose studies available (with Synthetic Graphite and Expanded Graphite powder) the low dose represented the NOAEL, where no adverse histopathological effects were found in the low dose, which can be understood as an absence of cytotoxicity. Hence, no additional assessment factor was applied, i.e. AF=1 was chosen.

b) Interspecies differences

The default assessment factor foreseen in ECHA Guidance on CSA for interspecies differences is 2.5 for local effects on the respiratory tract. According to available literature (Mermelstein et al., Lung Overload, Dosimetry of Lung Fibrosis and Their Implications to the Respiratory Dust Standard, Ann. occup. Hyg. Vol 38, Suppl. 1, pp 313 -322, 1994) lung overload is a general phenomenon occurring in most species and its onset occurs at 1mg/g lung burden. Based on the MPPD a lung burden of 0.45mg/lung (approx. 0.3mg/g lung) was calculated for the low dose (12mg/m3) of Synthetic Graphite powder. This dose represented the NOAEL of this repeated dose study (i.e. 20 exposure days). Compared to a hypothetical exposure of man to the same Synthetic Graphite powder at a concentration of 1.5mg/m3 (which is half of current occupational exposure levels), for 20 exosure days, 8hrs of exposure per day, respiratory rate of 8.4L/min, a lung burden of 16.8mg/lung (i.e. 0.0168mg/g lung) is calculated for man according to the MPPD model. This is well below the 1mg/g lung which is indicative for lung burden, as well as well below (about 18 times) the lung burden calculated for the experimental animals. Additionally taking into account that 1.5mg/m3 is higher than the calculated DNEL for inhalation it is prudent to deviate from the proposed AF of 2.5 and apply no additional AF, i.e. AF=1.

As for inhalation, long-term, local: two inhalation studies were conducted: Synthetic Graphite and Expanded Graphite

Two qualities of Graphite were considered for the present registration dossier: Synthetic Graphite (SG) and Expanded Graphite (EG). Both are high purity graphite qualities with SG having the higher purity (>99%) and no amounts of quartz or any other crystalline impurities. EG however may contain certain (but low) amounts of quartz (typical quantity: 0.9%) and muscovite (typical quantity: 1.2%), hence making it the slightly more adverse test item for inhalation exposure. However, results after repeated dose inhalation indicated that both qualities are similar in their effects - both qualities the NOAEL was equalling the low dose. Due to a different dosing scheme (please see IUCLID5 file) the low dose of EG was slightly lower, i.e. 8mg/m3 vs. 12mg/m3 for SG. Since both studies showed quite similar results and because of the relatively low Quartz-content of EG, 12mg/m3 was chosen as the effect level for calculation of the DNEL. Supportive for this assumption is, that EG was used in all other studies, none of which showed an adverse outcome. Additionally, the DNEL calculated from SG-NOAEL is more stringent than the recent occupational exposure limit for poorly soluble substances, providing a sufficient level of safety.

Additional Information

Expanded Graphite powder, DNEL worker, inhalation, local effects: 0,8mg/m3

Overall Assessment Factors: 5 (Applied Assessment Factors: Dose Descriptor (LOAEL/NOAEL): 1; Interspecies differences: 1; Intraspecies differences: 5; Duration of repeated dose study: 1; Qualitiy of whole database: 1; Dose descriptor modified according to ECHA Guidance)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Not systemically available after inhalation, hence no DNEL derived. Not classified as acute toxic via inhalation.

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Not systemically available after inhalation, hence no DNEL derived. Not classified as acute toxic via inhalation.

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Graphite is not expected to be systemically available via dermal exposure. Not classified as skin- or eye-irritant. After oral administration no toxicity observed up to the limit dose in an acute toxicity study, as well as in a repeated dose study (OECD 422). Therefore, no calculation of a DNEL.

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Graphite is not expected to be systemically available via dermal exposure. Not classified as skin- or eye-irritant. After oral administration no toxicity observed up to the limit dose in an acute toxicity study, as well as in a repeated dose study (OECD 422). Therefore, no calculation of a DNEL.

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
813 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Assessment factors

See discussion section "Workers".

Rationale for deviation from standard factors as given in ECHA Guidance on CSA

See discussion section "Workers".

As for DNELoral, long-term, general population no additional AFs were selected for interspecies differences and intraspecies differences, as well as for duration of exposure. This is justified, because due to the physico-chemical properties (e.g. water solubility and particle size) of Graphite it is highly unlikely that Graphite can be absorbed after oral administration, resulting in virtually no bioavailability. This scientific assumption is also supplemented by results from the OECD 422 study, where nominal doses up to 1000 mg/kg bw/day were well tolerated and did not show any sign for systemic toxicity. Since the study was conducted as a combined repeated dose toxicity study with the reproductive/developmental toxicity screening test, several NOAELs were obtained, all representing the nominal dose of 1000 mg/kg bw/day. However, the actual substance intake varied from about 813 mg/kg bw/day up to 1159 mg/kg bw/day. DNELs were calculated using the NOAEL of 813 mg/kg bw/day.

As for inhalation, long-term, local: two inhalation studies were conducted: Synthetic Graphite and Expanded Graphite

See discussion section "Workers".

Additional Information

Expanded Graphite powder, DNEL general population, inhalation, local effects: 0,2mg/m3

Overall Assessment Factors: 10 (Applied Assessment Factors: Dose Descriptor (LOAEL/NOAEL): 1; Interspecies differences: 1; Intraspecies differences: 10; Duration of repeated dose study: 1; Qualitiy of whole database: 1; Dose descriptor modified according to ECHA Guidance)