Registration Dossier

Administrative data

Description of key information

Repeated dose study: oral

- One study according to OECD 422 (subacute) was conducted

- Concentrations tested were up to the limit dose specified in OECD 422 = 1000mg/kg bw/day (nominal)

- No effects due to Graphite exposure were found, neither on systemic toxicity nor on reproductive/developmental toxicity

Repeated dose study: inhalation

- Two studies according to OECD 412 (subacute) were conducted

- Synthetic Graphite (SG; w/o Quartz) and Expanded Graphite (EG; with Quartz) were compared separately

- Testing of SG resulted in a NOAEL of 12 mg/m3, whereas testing of EG resulted in a NOAEL of 8 mg/m3

- Both qualities showed effects that were to be expected for a poorly soluble dust with low toxicity, with partly recovery after 28 days

- Exposure was generally well tolerated

- Despite the respiratory system no other organs were affected at all

- No sign of systemic toxicity was observed

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
813 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
12 mg/m³
Study duration:
subacute
Species:
rat

Additional information

Repeated dose study (28 -days) via oral route of exposure

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 a worst-case scenario for studies on inhalation exposure. To clarify whether there are substantial differences in effect, two separate repeated dose inhalation studies were conducted, one testing EG and one testing SG.

In the present study oral administration up to the limit concentrations as specified in OECD 422 no sign for systemic toxicity was found. Since SG does not contain any impurities that may be problematic after oral administration, obtained results are valid for SG as well.

Since the present 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

Repeated dose study (28 -days) via inhalation

As specified above, two sub-acute repeated dose inhalation studies were conducted, one with EG (containing quartz) and one with SG (not containing quartz). However, results after repeated dose inhalation indicated that both qualities, SG and EG are similar in their effects - in both qualities the NOAEL was equalling the low dose chosen for the respective studies. Due to a different dosing scheme (please refer to IUCLID5 file for details) the low dose of EG was slightly below the low dose of SG, i.e. 8mg/m3 vs. 12mg/m3. Since both studies showed quite similar results with respect to histopathological evaluation (please refer to IUCLID5 file for details) and because of the relatively low Quartz-content of EG, the SG NOAEL of 12mg/m3 was chosen as the effect level for calculation of the DNEL. Supportive for this assumption is, that EG was used as a test item in all other studies, none of which showed an adverse outcome. Additionally, the DNEL calculated from SG-NOAEL is well below the recent occupational exposure limit for poorly soluble substances, providing a sufficient level of safety.

Justification for classification or non-classification

Repeated dose study (28 -days) via oral route of exposure

Testing up to the nominal limit concentration as specified in OECD 422, i.e. 1000 mg/kg bw/day showed no signs of neither systemic toxicity nor any effects on reproductive/developmental toxicity.

Repeated dose study (28 -days) via inhalation

Based on the available 28 -day nose-only inhalation studies a NOAEL of 8 mg/m3 or 12mg/m3 could be derived based on the histopathological examination of the respiratory tract. However, these findings need to be assessed for their relevance in humans. There is ample evidence that rats show more severe effects as a reaction to respiratory particle overload than man. In accordance with Regulation (EC) No 1272/2008, Annex I, 3.9.2.8.1 (e) classification for specific target organ toxicity after repeated exposure (STOT-RE) shall not be justified, if substance-induced species-specific mechanisms of toxicity are not relevant for human health. The respective guidance on Regulation (EC) No 1272/2008 recognizes for this matter that “The relevance of lung overload in animals to humans is currently not clear and is subject to continued scientific debate.”. Taking these references into account in addition to the fact that Expanded Graphite powder showed effects that were to be expected for a poorly soluble dust, classification as STOT-RE is not justified.