General Comments
NBCI (Nanotechnology Business Creation Initiative) is a Japanese institution
established in 2003 to launch and expand the nanotechnology business. NBCI is
made up of more than 140 Japanese organizations interested in nanotechnology,
promoting the collection and sharing of the latest technical and environmental
safety information, and networking with industry, academia and government.
Furthermore, we are making recommendations on R & D strategies, environmental
safety regulations, and standardization activities in the field of nanotechnology.
Basically, we do not agree to evaluate several MWC(N)Ts as a group, because thegrouping is not sufficiently justified in the conclusions generalized in the CLH report(Please also see the comment on hazard classes).
Furthermore, we think that the current identity of the substance is unclear andshould be clarified to use for regulatory purposes. From the current identity, wecannot identify which substance is in the scope of harmonization, which thecompany needs to respond to.
- For the numerical values in the report, “a geometric tube diameter range ≥ 30 nm
to <3 μm and a length ≥ 5 μm and aspect ratio >3: 1,” it is not clear whether theserefer to the average values (substance meets the identity of the proposal if theaverage values are in the range of these values) or the values are for the individual
fiber (substance meets the identity of the proposal if one or more fibers is in therange of these values).
Therefore, we propose to include the percentage in the identity of the substance asfollows, for example using 80% or more which is the definition of mono-constituent
in the REACH and CLP regulations;“Multi-Walled Carbon Tubes (synthetic graphite in tubular shape), for 80 % ormore of the fibers is in the size range with a geometric tube diameter range ≥30 nm to <3 μm and a length ≥ 5μm and aspect ratio >3:1, including Multi-Walled
Carbon Nanotubes, MWC (N)T”
A similar idea is adopted in the definition of nanomaterials, which we believe is amore clear definition.
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- The following substances are cited in Table 11 of the CLH Report but are notconsidered to be “synthetic graphite.” Synthetic graphite is defined by IUPAC*1 as“A material consisting of graphitic carbon which has been obtained by graphitizingof non-graphitic carbon by chemical vapour deposition (CVD) from hydrocarbons attemperatures above 2500 K, by decomposition of thermally unstable carbides or by
crystallizing from metal melts supersaturated with carbon.”- CNT-7 and Short CNT-7: annealed at 1500°C, which are not graphitized (Huauxet al., 2016).
- MWCNT A, MWCNT B, MWCNT C, and MWCNT D: synthesis at the temperature of
850–1150°C, which are not graphitized (Rittinghausen et al., 2014).
As detailed above, the substances are clearly not in the scope of the substanceidentification of “Multi-Walled Carbon Tubes (synthetic graphite in tubular shape)with a geometric tube diameter range ≥ 30 nm to <3 μm and a length ≥ 5 μm andaspect ratio >3:1, including Multi-Walled Carbon Nanotubes, MWC(N)T.” Therefore,
the study data generated with those substances cannot be considered in thedetermination of classifications in the Proposal for Harmonised Classification andLabelling. Each reference in the CLH Report should be re-evaluated based on theproduction process (i.e., graphite or not), and the identity of the substance should
be address appropriately.
In conclusion, we cannot agree to evaluate several MWC(N)Ts as a group.
Furthermore, the current substance identity is not appropriate to gather commentsfrom companies that may have concerns.
*1

IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book").

Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications,
Oxford (1997). Online version (2019-) created by S. J. Chalk. ISBN 0-9678550-98. https://doi.org/10.1351/goldbook.

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Comments on the open hazard classes: Carcinogenicitya) IARC evaluation
The 11 studies are cited in the CLH Report Table 11, but these reports do not clearlysupport the classification of MWC(N)T as Carc. 1B
The IARC evaluated MWCNTs and classified MWNT-7 under the carcinogenic
category 2B and other MWCNTs under the carcinogenic category 3. In the CLH
report, there are new studies for MWNT-7 that show carcinogenicity in animals,
which strengthen the classification for MWNT-7 as a carcinogen. For otherMWC(N)Ts, some materials show carcinogenicity in animals but there is only one
experimental data for each material, thus the evidence is not sufficient for theclassification. Therefore, the newly evaluated studies in the CLH report dostrengthen the classification for MWNT-7 as a carcinogen, but these do not provide
sufficient evidence for extending the classification to other MWC(N)Ts with WHO
fiber dimensions.
In conclusion, the current situation (evidence of carcinogenicity) is the same as thesituation where IARC made the conclusion separately for MWNT-7 and otherMWC(N)Ts. We strongly support the IARCʼs conclusion that MWNT-7 has sufficientevidence and other MWC(N)Ts have limited evidence for carcinogenicity, which in
the CLP criteria, would be Carc. 1B for MWNT-7 and not Carc. 1B for other
MWC(N)Ts.
b) Classification of MWC(N)T as Carc. 1B
The CLH report proposed grouping several MWC(N)Ts into one group on theassumption that they have the same hazard. However, there is insufficientjustification to group substances of different manufacturing methods or sizes(diameter/length) under the same hazard group.
In “Appendix for nanoforms applicable to the Guidance on Registration andsubstance identification,” the document states that justification shall be provided
for the “set of similar nanoforms” as follows;“According to Annex VI of REACH: A 'set of similar nanoforms' is a group ofnanoforms characterised in accordance with section 2.4 where the clearly definedboundaries in the parameters in the points 2.4.2 to 2.4.5 of the individual nanoforms
3within the set still allow to conclude that the hazard assessment, exposure
assessment and risk assessment of these nanoforms can be performed jointly. A
justification shall be provided to demonstrate that a variation within theseboundaries does not affect the hazard assessment, exposure assessment andrisk assessment of the similar nanoforms in the set. A nanoform can only belong
to one set of similar nanoforms.”
Although this is the guidance for the registrants, we think that the same approachshould be applied for the CLH proposal. For example, the above guidance states theminimum justification that registrants should include in their reports:- How does the particle size of the different nanoforms impact the dissolution rateand solubility of the set members?
- How does the particle size of the different nanoforms within the set impact thetoxicokinetic behaviour as well as fate and (bio)availability of the set members?
- How does the particle size of the different nanoforms within the set impact the(eco)toxicity of the set members? Is there a direct relationship between theparticle size and the (eco)toxicity?
The guidance also states as follows for elongated nanoforms;- The width, together with length, is considered as a critical parameter that can beused as an indication of the rigidity of these nanoforms. Consideration on rigidity
is therefore linked to the requirement on particle size distribution in point 2.4.2of Annex VI of REACH and the registrant must justify how the variation inwidth of the particles of the different forms will affect the rigidity of theparticles and consequently the (eco)toxicological profile of the different
nanoforms. When there is a variability in the width of the particles constituting
the nanoforms covered by the set, the registrant must provide a justification
demonstrating that this variation does not affect the joint hazard
assessment of these nanoforms.
- The registrant must also take into account variations in the length and aspectratio of elongated particles when building the set of nanoforms. When there is avariation in length and/or aspect ratio of the particles of the nanoforms coveredby the set, the registrant must provide a justification demonstrating that
this variation does not affect the joint hazard assessment of thesenanoforms.

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As previously mentioned above, most of the data in the current CLH report is for
MWNT-7, and we think that the current CLH report critically lacks the description
for the justification of the grouping. For example, the following literature shows thatthe grouping is not appropriate.
- Results published by Nagai et al. (2011) demonstrate that the geometric tube
diameter is an important parameter for inducing injury to human mesothelial cells.
The ability of MWCNTs to pierce cell membranes is inversely proportional to its
diameter, i.e., the thinner the MWCNTs, the more likely they are to penetrate cellmembranes and develop mesotheliomas (see table below). Thus, it is inappropriate
to assume that several MWC(N)Ts are of the same hazard, given the evidence thatthe degree of carcinogenicity varies with size (diameter).
NT50a

NT115

NT145

NTtnglDiameter [nm]

49.95

116.2

143.5

N.D.

Piercing mesothelialYes

Low

Very low

NoneHighN.D.

Low

None

cell membranes
Carcinogenicity torats
N.D.: Not determined
From the above, we believe that each MWC(N)T should be evaluated separately.
When evaluating each material separately, we agree that MWNT-7 meets thecarcinogenicity Category 1B of the CLP criteria, since there is clear evidence
obtained by the inhalation study (OECD 451 with CLP compliance) and several
supporting studies. On the other hand, for other MWC(N)Ts, there is only one study
each that shows carcinogenicity. In addition, these studies have several substantial
deviations from the standard test guideline used in regulatory purposes;- the route of exposure is intraperitoneal, transtracheal, or intrascrotal instillation
whereas inhalation is the preferred route in the guideline for inhalable test materials,- the dosing regime (only one or several instillations in the early part of the study)
does not satisfy the provision of the guideline that states that the exposure should
cover the major part of the life span of the test animals,- the non-physiological dosing with a single treatment or several treatments results
in a local bolus dose leading to excess evaluation.
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Therefore, we believe that a single study with several substantial deviations should
not be treated as “sufficient evidence” of carcinogenicity.
In conclusion, since there is a lack of justification to group the substance in one
category, we think the materials should be evaluated separately. It can be agreed
that MWNT-7 is classified as Carc. 1B, but other MWC(N)Ts should not be classified
as Carc. 1B.

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