Registration Dossier

Toxicological information

Acute Toxicity: other routes

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Administrative data

Endpoint:
acute toxicity: other routes
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
other: 2 (reliable with restriction) because study meets the requirements of research purposes but is not suitable for regulatory hazard assessment
Rationale for reliability incl. deficiencies:
other: Study meets the requirements of research purposes but is not suitable for regulatory hazard assessment

Data source

Reference
Reference Type:
publication
Title:
Enhanced peripheral thrombogenicity after lung inflammation is mediated by platelet–leukocyte activation: role of P-selectin
Author:
Nemmar, A. et al.
Year:
2007
Bibliographic source:
Journal of Thrombosis and Haemostasis 5, 1217–1226

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The aim of the study was to investigate how lung inflammation induced by pulmonary carbon nanotubes would translate into a circulating prothrombotic tendency, enhancing the risk for thrombosis, in cases of peripheral vascular lesions.

GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
mouse
Strain:
Swiss
Sex:
male/female

Administration / exposure

Route of administration:
other: intratracheal instillation
Vehicle:
other: sterile 0.9% saline containing 0.1% Tween 80
Details on exposure:
40 µL/animal
Doses:
200 or 400 µg/animal
No. of animals per sex per dose:
no data
Control animals:
other: vehicle
Details on study design:
BALF: 24 hours after CNT administration, the animals were sacrificed and bronchoalveolar lavage (BAL) was performed.
Cell differentials were microscopically performed.

Additionally the following investigation were performed:

Granulocyte–platelet heteroconjugate detection

Thrombin generation and microvesicle activity detection

Whole murine blood platelet aggregation assays

In vivo P-selectin neutralization

Experimental arterial thrombosis model

Tail and jugular vein bleeding time measurements

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
other: lung inflammation
Effect level:
200 - 400 other: µg/mouse
Remarks on result:
other: rapid, but mild and transient, circulating platelet activation, triggering P-selectin-mediated platelet-leukocyte conjugate formation
Mortality:
no data
Clinical signs:
no data
Body weight:
no data
Gross pathology:
no data

Any other information on results incl. tables

"Intratracheal instillation in Swiss mice of 200 and 400 µg of multiwall ground CNTs triggered substantial

lung neutrophil, but not macrophage influx, 24 h later. The detection of circulating platelet–leukocyte conjugates exclusively 6 h after CNT instillation pointed to early but transientactivation of circulating platelets. At 24 h, elevated plasma procoagulant microvesicular tissue factor activity was found in CNT-exposed but not in saline-exposed mice. However, at 24 h, both the tail and jugular vein bleeding times were prolonged in CNT-exposed but not in saline-exposed mice, arguing against strong CNT-induced platelet activation at this point. Nevertheless, at 24 h, enhanced peripheral thrombogenicity was detected in CNT-exposed but not in saline-exposed mice, via quantitative photochemically induced carotid artery thrombosis measurements. P-selectin neutralization abrogated platelet–leukocyte conjugate formation and microvesicular tissue factor generation, and abolished the CNT-induced thrombogenicity amplification. In contrast, the weak vascular injury-triggered

thrombus formation in saline-treated mice was not affected by P-selectin neutralization at 24 h."

Applicant's summary and conclusion

Executive summary:

The ground test substance meeting the form described in section 4.5 of the IUCLID dossier was administered intratracheally (200, 400 µgmg/animal) to Swiss mice to evaluate how pulmonary inflammation enhancing the risk for thrombosis, in cases of peripheral vascular lesions.

"The mild lung inflammation induced by the test substance meeting the form described in section 4.5 of the IUCLID dossier translates via rapid but mild and transient activation of platelets into P-selectin-mediated systemic inflammation. Leukocyte activation leads to tissue factor release, in turn eliciting inflammation-induced procoagulant activity and an associated prothrombotic risk."