Registration Dossier

Administrative data

Workers - Hazard via inhalation 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:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
2
Dose descriptor:
NOAEC
Value:
0.1 mg/m³
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

Based on current knowledge on hazard of MWCNT meeting the form described in section 4.5 of the IUCLID dossier the acute oral and dermal toxicity studies did not reveal any specific toxicity in rats. As no mortality was observed after acute inhalation of the maximum technically attainable concentration of MWCNT, it can be concluded, that the LC50 is >241 mg/m³. No indications of systemic toxicity were found in this study. Inflammatory effects, as typical for poorly soluble particles, were observed. There was no evidence of skin irritation and sensitisation. Eye irritation was only mild and transient when examined in rabbits. The standard regulatory genotoxicity assays did not provide evidence of any genotoxic potential.

The respiratory tract is considered a major portal of MWCNT entry because of the likelihood that the MWCNT will become airborne during handling. As the local effects at the respiratory tract are the most sensitive effects and there is no indication of systemic toxicity, for workers DNEL long-term for inhalation route-local is derived.

The NOAEL of the repeated exposure 13-week inhalation study is solely dependent on localized effects occurring both at the pulmonary and nasal turbinate level. In rats exposed to 0.4 mg/m³, only borderline to minimal effects were observed and included focal inflammatory infiltrates, hypercellularity, and septal thickening with minimal focally increased collagen. Collective evidence supports the conclusion that 0.1 mg/m³ constitutes the NO(A)EL of this study based on nasal and pulmonary inflammatory responses, this means at the sites where predominant particle deposition occurs. The applied methodology for deriving a human indicative no-effect level starting from the NOAEL of the subchronic study is a mode-of-action-based, scientific approach which does not conform in all cases with the default modification and assessment factors of REACH guidance documents. But it should be noted that according to REACH guidance documents default values could be replaced by substance specific values, if sufficient information and a justification is provided.

The pursued approach is described in detail in two publications by Pauluhn (Regulatory Toxicology and Pharmacology 57, 78 -89 (2010) and Toxicology 279, 176 -188 (2011)).

Without going into details on how the different adjustment factors were calculated and explained the overall factor to be applied to the animal NOAEL (= 0.1 mg/m³) without further modification is 2, leading to an

DNELWorker, long-term – local, inhalation of 0.05 mg/m³.

  

OEL(TWA) = NOAELrat/AFretained Dose= 0.1 x ½ = 0.05 mg/m³

 

OEL Occupational exposure limit

TWA time weighted average

AF adjustment factor

 

In addition the abstract from the publication which focuses on derivation of an occupational exposure limit for MWCNT is displayed below:

"This MWCNT has been examined in previous single and repeated exposure 13-week rat inhalation studies. Kinetic endpoints and the potential to translocate to extrapulmonary organs have been examined during postexposure periods of 3 and 6 months, respectively. The focus of both studies was to compare dosimetric endpoints and the time course of pulmonary inflammation characterized by repeated bronchoalveolar lavage and histopathology during the respective follow-up periods. To better understand the etiopathology of pulmonary inflammation and time-related lung remodeling, two metrics of retained lung dose were compared. The first used the mass metric based on the exposure concentration obtained by filter analyses and aerodynamic particle size of airborne MWCNT. The second was based on calculated volumetric lung burdens of retained MWCNT. Kinetic analyses of lung burdens support the conclusion that Baytubes, in principal, act like poorly soluble agglomerated carbonaceous particulates. However, the difference in pulmonary toxic potency (mass-based) appears to be associated with the low-density (approx. 0.1– 0.3 g/m3) of the MWCNT assemblages. Of note is that assemblages of MWCNT were found predominantly both in the exposure atmosphere and in digested alveolar macrophages. Isolated fibers were not observed in exposure atmospheres or biological specimens. All findings support the conclusion that the low specific density of microstructures was conducive to attaining the volumetric lung overload-related inflammatory response conditions earlier than conventional particles. Evidence of extrapulmonary translocation or toxicity was not found in any study. Thus, pulmonary overload is believed to trigger the cascade of events leading to a stasis of clearance and consequently increased MWCNT doses high enough to trigger sustained pulmonary inflammation. This mechanism served as conceptual basis for the calculation of the human equivalent concentration. Accordingly, multiple interspecies adjustments were necessary which included species-specific differences in alveolar deposition, differences in ventilation, and the time-dependent particle accumulation accounting for the known species-specific differences in particle clearance half-times in rats and humans. Based on this rationale and the NOAEL (no-observed adverse effect level) from the 13-week subchronic inhalation study on rats, an occupational exposure limit (OEL) of 0.05 mg Baytubes/m3 (time weighted average) is considered to be reasonably protective to prevent lung injury to occur in the workplace environment." (Cited from Pauluhn J., Regulatory Toxicology and Pharmacology 57, 78 -89 (2010))

 

General Population - Hazard via inhalation 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
DNEL related information

General Population - 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

General Population - Hazard via oral 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

In all applications of MWCNT that are relevant to the general population, MWCNT are firmly incorporated in material matrices. (SCENIHR (2006) Modified opinion SCENIHR/002/05, p.16) was of the opinion that nanoparticle aerosols arising from mechanical processes (e.g. the breaking or fracture of solid or liquid material) are unlikely to be formed and that grinding and surface finishing typically releases micrometre and submicrometre particles, possibly down to 100 nm but rarely below this. This opinion is supported by later experimental investigations published in the literature. Vorbau et al. (Journal Aerosol Science 40, 3 , 209-217, 2009) could not detect any release of the nanoparticles incorporated in coating matrices during a mechanical abrasion process. No release of carbon nanotubes was detected after abrasion of polymers such as PEEK containing carbon nanotubes (TRACER project sponsored by German Federal Ministry of Education and Research (BMBF, 2009). No carbon nanotubes, either individual or in bundles, were observed in extensive electron microscopy of collected samples by dry and wet machining abrasive of composite containing carbon nanotubes ( Bello et al. (2009) J. Nanopart. Res. 11:231-249).

Thus, exposure of the general population to MWCNT is considered to be negligible and therefore no DNEls were derived for the general population.