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Comment from on presentation

by A. Lecloux, Nanocyl

Ken DonaldsonProfessor of Respiratory Medicine

The Queens Medical Research Institute The University of Edinburgh

&Honorary Principal Scientist

Institute of Occupational MedicineEdinburgh

Excerpts from the Lecloux presentation in Blue Arial

KD comments in Black Tekton

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Particle and short fibre effects

alveolar inflammation, fibrosis, cancer, exacerbations airways disease, deaths hospitalisations for cardiovascular disease?

Particle type effects

Particle and short fibre effects

alveolar inflammation, fibrosis, cancer, exacerbations airways disease, deaths hospitalisations for cardiovascular disease?

Particle type effects

Aimed at showing ability to cause inflammation, lung cancer, scarring, cardiovascular endpoints

Carbon nanotubes could cause a particle and/or a fibre hazard

Nanotubes in particle form

Toxicology tests

Long fibre effects

alveolar inflammation, interstitial fibrosis, cancer

pleural effusion, pleural fibrosis, mesothelioma

Long fibre type effects in the lungs

Long fibre type effects in the pleura

Long fibre effects

alveolar inflammation, interstitial fibrosis, cancer

pleural effusion, pleural fibrosis, mesothelioma

Long fibre type effects in the lungs

Long fibre type effects in the pleura

All those caused by particles plus effects on the pleura and the mesothelium, which are SPECIFIC for long fibres

Nanotubes in long fibre form

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ELEGIELEGINegative carcinogenic test in rats during 2 years (published)

• This test was carried out in the rat peritoneal cavity to determine whether CNT would cause mesothelioma

• This is a test for long fibres and only long fibres cause mesothelioma

• The average length of the Nanotubes was about a micron – this is very short

• So it is no surprise that there was ‘absence of a carcinogenic response’after short fibres

• For short fibres and other particles the lung is the target not the body cavity lining and lung cancer is the hazard not mesothelioma

• The obvious place to look for carcinogenic effects of short nanotubes is the lungs, not the peritoneal cavity

• Muller et al was not a well-designed carcinogenicity test for short CNT; it tells us nothing about the potential carcinogenicity of short CNT like the Nanocyl CNT

(Muller, J., Delos, M., Panin, N., Rabolli, V., Huaux, F., and Lison, D. (2009). Absence of carcinogenic response to multi-wall carbon nanotubes in a 2-year bioassay in the peritoneal cavity of the rat. Toxicological Sciences kfp100.)

SLIDE 14

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ELEGIELEGIOnly a small fraction of CNTs

is inhalable

But difficulties in measuring particle size distribution in the nano range

So why make the statement ‘Only a small fraction of CNT is inhalable’? –potentially misleadingTo solve this problem the Naneum company (UK) developed portable sampling devices covering particle sizes from 3 nm up to 30 microns

So what did this instrument show for the particle number throughout the size ranges?

SLIDE 15

By common consent likely the most important metric is not volume (mass) but number or surface area

Num

ber

Surf

aace

area

Mas

s

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The CNT concentrations measured in air are 1.45 µg CNT/m³ at the packaging1 µg CNT/m³ in extruder room 0.25µg CNT/m³ in R&D offices

Is the problem of measuring CNT in air now solved?

Exposure is a dynamic and changing entity dependent on behaviour and conditions in the workspace and a single measurements is not sufficient

If more than one was done then an indication of the average, the standard deviation and range need to be show; peaks could be important

Slide 16 is all about how difficult it is to measure CNT in air- the impression given is that methodology is still in development (see bullet point 5) yet we next find a single measurement of CNT in air for 3 sites

SLIDE 16

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Han JH, Lee EJ, Lee JH, So KP, Lee YH, Bae GN, Lee SB, Ji JH, Cho MH, Yu IJ.Monitoring multiwalled carbon nanotube exposure in carbon nanotube research facility. Inhal Toxicol. 2008 Jun;20(8):741-9.

• Study monitored the possible exposure to MWCNT release in a carbonnanotube research laboratory.

• The gravimetric concentrations of total dust before any control measuresranged from 0.21 to 0.43 mg/m(3),

• The number of MWCNTs in the samples obtained from the MWCNT blending laboratory ranged from 172.9 to 193.6 MWCNTs/cc before thecontrol measures,

• Decreased to 0.018-0.05 MWCNTs/cc after the protective improvements.

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ELEGIELEGISLIDE 19

•So the impression is given that a no effect concentration of 2.5µg/m3 obtains

•And that the measured concentration was 1.5µg/m3 (a single measurement!)

•We know that the levels of particles in air is changing constantly and no single figure is useable

•We need to know the variability around 1.5 µg/m3

• If it’s a mean then there must have been measurements above it and if its not a mean what is it?

•In any case, there are always peaks and

• Measured level of 1.5 and a NOEL of 2.5 are too close for my comfort

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ELEGIELEGICarbon nanotubes could be a particle and/or a fibre hazard; if nanotubes are long and straight then we need to address the

long fibre (asbestos-type) hazard

Nanocyl nanotubes may be short/tangled but for other production plants there needs to be some screening to determine whether the CNT in the air are long and straight so the right hazard can be assessed

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Summary

Mixed messages-Avowed ‘willingness to be transparent’ as to risks yet:-

• Focus on volume (mass) as exposure metric when number and SA are considered to be most important

•Acknowledge its difficult to measure CNT in air but a single figure is given for exposure when exposure is a notoriously variable entity

•A ‘risk assessment’ is made and compared to a single measure of exposure which turns out to be less than twice the estimated NOAEL (see above)

•The composition is important by Nanocyl’s own studies so how generic is this for other short nanotube formulations

•A carcinogenicity study based on long fibre hazard is cited that is irrelevant to Nanocyl tubes which are short/tangled and so are a particle-type hazard

•Therefore there is no validated study on the carcinogenicity of the nanocylnanotubes in the relevant target organ - the lungs

This paper was produced for a meeting organized by Health & Consumers DG and represents the views of its author on thesubject. These views have not been adopted or in any way approved by the Commission and should not be relied upon as a statement of the Commission's or Health & Consumers DG's views. The European Commission does not guarantee the accuracy of the dataincluded in this paper, nor does it accept responsibility for any use made thereof.