1 
 EN 
 
ANNEX  
 
 
1. Annex I to Regulation (EC) No 1907/2006 is amended as follows:  
 
(a) Subsection 0.1. is replaced by the following:  
"0.1. The purpose of this Annex is to set out how manufacturers and importers are to 
assess and document that the risks arising from the substance they manufacture or 
import are adequately controlled during manufacture and their own use(s) and that 
others f urther down the supply chain can adequately control the risks. The chemical 
safety report shall also describe whether and which different nanoforms of 
substances as characterised in Annex VI  are manufactured and imported, including 
an adequate justificatio n for each information requirement describing when and how 
information on one form is used to demonstrate safety of other forms. The 
requirements specific to nanoforms of a substance in this Annex apply without 
prejudice to requirements applicable to other  forms of that substance. This Annex 
shall also apply adapted as necessary to producers and importers of articles required 
to make a chemical safety assessment as part of a registration .";  
(b) Subsection 0.3. is replaced by the following:   
"0.3. The chemi cal safety assessment of a manufacturer shall address the 
manufacture of a substance and all the identified uses. The chemical safety 
assessment of an importer shall address all identified uses. The chemical safety 
assessment shall consider the use of the substance on its own (including any major 
impurities and additives), in a mixture and in an article, as defined by the identified 
uses. The assessment shall consider all stages of the life -cycle of the substance 
resulting from the manufacture and identifie d uses. The assessment shall address 
nanoforms that are covered by the registration. The justifications and conclusions 
drawn from the assessment shall be relevant to these nanoforms.  The chemical safety 
assessment shall be based on a comparison of the potential adverse effects of a 
substance with the known or reasonably foreseeable exposure of man and/or  the 
environment to that substance taking into account implemented and recommended 
risk management measures and operational conditions. "; 
(c) Subsection 0.4. is replaced by the following:  
"0.4. Substances whose physicochemical, toxicological and eco -toxicological 
properties are likely to be similar or follow a regular pattern as a result  of structural 
similarity may be considered as a group, or ‘category’ of substances. If the 
manufacturer or importer considers that the chemical safety assessment carried out 
for one substance is sufficient to assess and document that the risks arising fro m 
another substance or from a group or ‘category’ of substances are adequately 
controlled then he can use that chemical safety assessment for the other substance or 
group or ‘category’ of substances. The manufacturer or importer shall provide a 
justificati on for this. Where  any of the substances exists in one or more nanoforms 
and data from one form are used in demonstration of the safe use of other forms, in 
accordance with the general rules set out in Annex XI, a scientific justification shall 2 
 be given on  how, applying the rules for grouping and read -across, the data from a 
specific test or other information (e.g. methods, results or conclusions) can be used 
for the other forms of the substance. Similar considerations apply to exposure 
scenarios and risk m anagement measures ."; 
(d) The last paragraph in subsection 0.5. is replaced by the following:  
"If the manufacturer or importer considers that further information is necessary for 
producing his chemical safety report and that this information can only be o btained 
by performing tests in accordance with Annex IX or X, he shall submit a proposal for 
a testing strategy, explaining why he considers that additional information is 
necessary and record this in the chemical safety report under the appropriate headin g. 
Where considered necessary, the proposal for a testing strategy may concern several 
studies addressing respectively different forms of the same substance for the same 
information requirement. While waiting for results of further testing, he shall record  
in his chemical safety report, and include in the exposure scenario developed, the 
interim risk management measures that he has put in place and those he recommends 
to downstream users intended to manage the risks being explored. The exposure 
scenarios an d interim risk management measures recommended shall address 
nanoforms that are covered by the registration. "; 
(e) Point 0.6.3 is replaced by the following:  
"0.6.3. Where as a result of steps 1 to 4 the manufacturer or importer concludes that 
the substanc e or, when applicable, nanoforms thereof fulfils the criteria for any of the 
following hazard classes or categories set out in Annex I to Regulation (EC) No 
1272/2008 or is assessed to be a PBT or vPvB, the chemical safety assessment shall 
also include ste ps 5 and 6 in accordance with Sections 5 and 6 of this Annex:  
(a) hazard classes 2.1 to 2.4, 2.6 and 2.7, 2.8 types A and B, 2.9, 2.10, 2.12, 2.13 
categories 1 and 2, 2.14 categories 1 and 2, and 2.15 types A to F;  
(b) hazard classes 3.1 to 3.6, 3.7 advers e effects on sexual function and fertility or on 
development, 3.8 effects other than narcotic effects, 3.9, and 3.10;  
(c) hazard class 4.1;  
(d) hazard class 5.1. "; 
(f) After subsection 0.11. the following subsection 0.11.bis is added:  
"0.11.bis When nanof orms are covered by the chemical safety assessment, an 
appropriate metric for the assessment and presentation of the results in steps 1 -6 of 
the chemical safety assessment under 0.6.1 and 0.6.2 shall be considered, with the 
justification included in the ch emical safety report and summarised in the safety data 
sheet. A multiple metric presentation, including mass metric information, is 
preferable. When possible, a method for reciprocal conversion shall be indicated. ";  
(g) The following sentence is added aft er the first line of section 1.0.3:  
"The assessment shall address nanoforms that are covered by the registration. ";   
(h) The second paragraph of point 1.3.1. is replaced by the following:  
"The assessment should always include a statement as to whether the substance or, 
when applicable, nanoforms thereof fulfils or does not fulfil the criteria given in 
Regulation (EC) No 1272/2008 for classification in the hazard class carcinogenicity 3 
 categor y 1A or 1B, in the hazard class germ cell mutagenicity category 1A or 1B or 
in the hazard class reproductive toxicity category 1A or 1B. "; 
(i) Point 1.3.2. is replaced by the following:  
"1.3.2. If the information is inadequate to decide whether a substance  or, when 
applicable, nanoforms thereof should be classified for a particular hazard class or 
category, the registrants shall indicate and justify the action or decision he has taken 
as a result. "; 
(j) The second paragraph of subsection 2.2. is replaced by  the following:  
"If the information is inadequate to decide whether a substance  or, when applicable, 
nanoforms thereof  should be classified for a particular hazard class or category, the 
registrant shall indicate and justify the action or decision he has taken as a result. ";  
(k) The following sentence is added at the end of point 3.0.2.:  
"The assessment shall address nanoforms when they are covered by the 
registration. ";  
(l) Point 3.2.1. is replaced by the following:  
"3.2.1. The appropriate classificati on developed in accordance with the criteria in 
Regulation (EC) No 1272/2008 shall be presented and justified. Any M -factor 
resulting from the application of Article 10 of Regulation (EC) No 1272/2008 shall 
be presented and, if it is not included in Part 3  of Annex VI to Regulation (EC) No 
1272/2008, justified.  
The presentation and justification is applied to nanoforms covered by the 
registration. ";  
(m) Point 3.2.2. is replaced by the following:  
"3.2.2. If the information is inadequate to decide whether a substance or, when 
applicable, nanoforms thereof should be classified for a particular hazard class or 
category, the registrant shall indicate and justify the action or decision he has taken 
as a result ."; 
(n) Point 4.0.2. is replaced by the following:  
"4.0.2. The PBT and vPvB assessment shall comprise the following two steps, which 
shall be clearly identified as such in Part B, Section 8 of the Chemical Safety report. 
The assessment shall address nanoforms when they are covered by the registration:  
Step 1 : Comparison with the Criteria.  
Step 2  : Emission Characterisation.  
The assessment shall also be summarised in the Safety Data Sheet under heading 
12.";  4 
 (o) Subsection 4.2. is replaced by the following:  
"4.2. Step 2: Emission Characterisation  
If the substance fulfils the criteria or it is considered as if it is a PBT or vPvB in the 
registration dossier an emission characterisation shall be conducted comprising the 
relevant parts of the exposure assessment as described in Section 5. In particular it 
shall contain an estimation of the amounts of the substance released to the different 
environmental compartments during all activities carried out by the manufacturer or 
importer and all identified uses, and an identification of the likely routes by whi ch 
humans and the environment are exposed to the substance . The estimation shall 
address nanoforms that are covered by the registration. ";  
(p) The first paragraph of subsection 5.0. is replaced by the following:  
"The objective of the exposure assessment shall be to make the quantitative and 
qualitative estimate of the dose/concentration of the substance to which humans and 
the environment are or may be exposed. The assessment shall consider all stages of 
the life -cycle of the substance resulting from the manufacture and identified uses and 
shall cover any exposures that may relate to the hazards identified in Sections 1 to 4. 
The assessment shall address nanoforms that are covered by the registration. The 
exposure assessment shall entail the following two steps, which shall be clearly 
identified as such in the Chemical Safety Report: ";  
(q) The following sentence is added at the end of point 5.2.2.:  
"When nanoforms are covered by the registration, the emission estimation for these 
shall, where relevant, tak e account of situations when the conditions outlined in Annex 
XI section 3.2 point (c) are fulfilled. "; 
(r) Point 5.2.3. is replaced by the following:  
"5.2.3. A characterisation of possible degradation, transformation, reaction processes, 
and an estimatio n of environmental distribution and fate shall be performed.  
When nanoforms are covered by the registration, a characterisation of particle 
aggregation, agglomeration and particle surface chemistry changes shall be included. " 5 
 2.  Annex III to Regulation (EC) No 1907/2006 is amended as follows:  
 
"CRITERIA FOR SUBSTANCES REGISTERED IN QUANTITIES BETWEEN 1 AND 
10 TONNES  
Criteria for substances and, when applicable, for nanoforms thereof,  registered between 1 and 
10 tonnes, with reference to Article 12(1)(a) and (b):  
(a) substances for which it is predicted (i.e. by the application of (Q)SARs or other 
evidence) that they a re likely to meet the criteria for category 1A or 1B classification 
in the hazard classes carcinogenicity, germ cell mutagenicity or reproductive toxicity 
or the criteria in Annex XIII;  
(b) substances:  
(i) with dispersive or diffuse use(s) particularly wh ere such substances are used 
in consumer mixtures or incorporated into consumer articles; and  
(ii) for which it is predicted (i.e. by application of (Q)SARs or other evidence) 
that they are likely to meet the classification criteria for any health or 
envir onmental hazard classes or differentiations under Regulation (EC) No 
1272/2008  or for substances with nanoforms, unless those nanoforms are 
soluble in biological and environmental media ." 
 6 
 3. Annex  VI to Regulation (EC) No 1907/2006 is amended as follows:  
 
(a) The introductory text under the subtitle 'Guidance note on fulfilling the requirements of 
annexes VI to XI' is replaced by the following:  
"Annexes VI to XI specify the information that shall be submitted for registration 
and evaluation purposes according to Articles 10, 12, 13, 40, 41 and 46. For the 
lowest tonnage level, the standard requirements are in Annex VII, and every time a 
new tonnage level is reached, the requirements of the corresponding Annex have to 
be added. For each registration the precise information requirements will differ, 
according to tonnage, use, and exposure. The Annexes shall thus be considered as a 
whole, and in conjunction with the overall requirements of registration, evaluation 
and the duty of care.  
A substance is defined in accordance with Article 3(1) and identified in accordance 
with section 2 in this Annex. A substance is always manufactured or imported in at 
least one form. A substance can also occur in more than one form.    
Where a substance b eing registered is also manufactured or imported in nanoform 
certain specific information items have to be provided. Nanoforms shall be 
characterised as provided in this Annex. Furthermore, the registrant of a substance 
with nanoforms shall justify why the  information provided in the joint registration is 
relevant to cover the information requirements for the registered substances with 
nanoforms. Information relevant to cover information requirements for such 
substance can also be submitted separately by in dividual registrants, where  they 
consider it justified in accordance with Article 11(3).  
More than one dataset may be required for one or more information requirements 
whenever there are significant differences in the properties relevant for the hazard, 
exposure and risk assessment and management for nanoforms of a substance. The 
information shall be reported in such a manner that it is clear what information in the 
joint submission pertains to which nanoform or set of nanoforms of the substance.  
The techn ically and scientifically justified methodologies set out in Annex XI.1.5 
shall be used within a registration dossier when two or more forms of a substance are 
'grouped' for the purposes of one, more or possibly all the information requirements.  
  7 
 Guidanc e note on nanoforms : 
In accordance with the Commission Recommendation of 18 October 2011 on the 
definition of nanomaterial1, a form of a natural or manufactured substance containing 
particles, in an unbound state or as an aggregate or as an agglomerate and  where, for 
50 % or more of the particles in the number size distribution, one or more external 
dimensions is in the size range 1 nm -100 nm, including also by derogation, 
fullerenes, graphene flakes and single wall carbon nanotubes with one or more 
externa l dimensions below 1 nm, is a nanoform of a substance. The term ‘nanoform’, 
when it is referred to in the other Annexes, shall relate to a nanoform or a set of 
nanoforms that has been characterised in accordance with section 2.4 below.  A 
substance may have  one or more different nanoforms , based on differences in the 
parameters in points 2.4.2 to 2.4.5 .  
For this purpose, ‘particle’ means a minute piece of matter with defined physical 
boundaries; ‘agglomerate’ means a collection of weakly bound particles or 
aggregates where the resulting external surface area is similar to the sum of the 
surface areas of the individual components and ‘aggregate’ means a particle 
comprising of strongly bound or fused particles2. 
The requirements specific to nanoforms apply wit hout prejudice to requirements 
applicable to other forms of a substance. The term ‘nanoform’, when it is referred to 
in the other Annexes, shall relate to an individual nanoform or a set of nanoforms 
when one has been defined in accordance with section 2.4  below. "; 
(b) Step 1  is replaced by the following:  
"STEP 1 – GATHER AND SHARE EXISTING INFORMATION  
The registrant should gather all existing available test data on the substance to be 
registered, this would include a literature search for relevant informat ion on the 
substance.  
Wherever practicable, registrations should be submitted jointly, in accordance with 
Articles 11 or 19. This will enable test data to be shared, thereby avoiding 
unnecessary testing and reducing costs. The registrant should also colle ct all other 
available and relevant information on the substance including on nanoforms of the 
substance when they are covered by the registration, regardless whether testing for a 
given endpoint is required or not at the specific tonnage level. This shoul d include 
information from alternative sources (e.g. from (Q)SARs, read -across from other 
substances, in vivo  and in vitro  testing, epidemiological data) which may assist in 
identifying the presence or absence of hazardous properties of the substance and 
which can in certain cases replace the results of animal tests.  
In addition, information on exposure, use and risk management measures in 
accordance with article 10 and this Annex should be collected. Considering all this 
information together, the registran t will be able to determine the need to generate 
further information. "; 
(c) Step 3 is replaced by the following:  
                                                 
 
 8 
 "STEP 3 – IDENTIFY INFORMATION GAPS  
The registrant shall then compare the information needs for the substance with the 
information already available and the extent to which currently available information 
can be applied to nanoforms covered by the registration and identify where there are 
gaps.  
It is important at this stage to ensure that the available data is relevant and has 
sufficient quality  to fulfil the requirements. ";  
(d) Step 4 is replaced by the following:  
"STEP 4 – GENERATE NEW DATA/PROPOSE TESTING STRATEGY  
In some cases it will not be necessary to generate new data. However, where there is 
an information gap that needs to be filled, n ew data shall be generated (Annexes VII 
and VIII), or a testing strategy shall be proposed (Annexes IX and X), depending on 
the tonnage. New tests on vertebrates shall only be conducted or proposed as a last 
resort when all other data sources have been exh austed.  
The above approach shall also apply if there is a gap of available information for one 
or more nanoforms of the substance included in the jointly submitted registration 
dossier.  
In some cases, the rules set out in Annexes VII to XI may require cert ain tests to be 
undertaken earlier than or in addition to the standard requirements.  
NOTES  
Note 1: If it is not technically possible, or if it does not appear scientifically 
necessary to give information, the reasons shall be clearly stated, in accordance with 
the relevant provisions.  
Note 2: The registrant may wish to declare that certain information submitted in the 
registration dossier is commercially sensitive and its disclosure might harm him 
commercially. If this is the case, he shall list the items a nd provide a justification. "; 
(e) The introductory text in Section 2 Identification of the substance is replaced by the 
following:  
"For each substance, the information given in this section shall be sufficient to enable 
each substance to be identified and the different nanoforms to be characterised. If it 
is not technically possible or if it does not appear scientifically necessary to give 
information on one or more of the items below, the reasons shall be clearly stated. "; 
(f) Subsection 2.3 . is replaced by the following:  
"2.3. Composition of each substance. Where a registration covers one or more 
nanoforms, these nanoforms shall be characterized pursuant to section 2.4 of this 
Annex.  
2.3.1. Degree of purity (%)  
2.3.2. Nature of impurities, including isomers and by -products  
2.3.3. Percentage of (significant) main impurities  
2.3.4. Nature and order of magnitude (… ppm, … %) of any additives (e.g. 
stabilising agents or inhibitors)  9 
 2.3.5. Spectral data (ultra -violet , infra -red, nuclear magnetic  resonance or mass 
spectrum)  
2.3.6. High -pressure liquid chromatogram, gas chromatogram  
2.3.7. Description of the analytical methods or the appropriate bibliographical 
references for the identification of the substance and, where appropriate, for the 
ident ification of impurities and additives. This information shall be sufficient to 
allow the methods to be reproduced.  
2.4. Characterisation of nanoforms of a substance: For any of the characteristics, the 
information provided may be applicable to individual n anoforms or sets of similar 
nanoforms provided that the boundaries of the sets are clearly specified. A 
justification shall be provided to demonstrate why the sets are appropriate for the 
hazard assessment, exposure assessment and risk assessment of the in dividual 
nanoforms  that are manufactured and placed on the market.  
The information in points 2.4.2 – 2.4.5 shall be clearly assigned to the different 
nanoforms or sets of similar nanoforms identified in point 2.4.1.  
2.4.1. Names or other identifiers of t he nanoforms or sets of similar nanoforms of the 
substance  
2.4.2. Particle number size distribution with indication of the number fraction of 
constituent particles in the size range 1 nm – 100 nm.  
2.4.3. Description of surface functionalization or treatme nt and identification of each 
agent including IUPAC name and CAS or EC number.  
2.4.4. Shape, aspect ratio and other morphological characterisation; information on 
assembly structure including e.g. shell like structures or hollow structures, if 
appropriate   
2.4.5. Surface area (specific surface area by volume , specific surface area by mass  or 
both) 
2.4.6. Description of the analytical methods or the appropriate bibliographical 
references for the identification of the information elements in this sub -section . This 
information shall be sufficient to allow the methods to be reproduced. "; 
(g) In section 3, the following introductory text is added after the title 'INFORMATION ON 
MANUFACTURE AND USE(S) OF THE SUBSTANCE(S)':  
"Where a substance being registered is manufactured or imported in one or several 
nanoforms, the information on manufacture and use under 3.1 -3.7 shall include 
separate information on the different nanoforms or sets of similar nanoforms as 
characterised in subsection 2.4. ";   
(h) In section 5, the introductory text is replaced by the following:  
"This information shall be consistent with that in the Safety Data Sheet where such a 
Safety Data Sheet is required according to Article 31.  
Where a substance being registered is also manufactured or imported in one or 
several nanoforms, the information pursuant to this Section shall address the 
different nanoforms or sets of similar nanoforms as characterised in subsection 2.4 
where relevant. "; 10 
 (i) In section 6, the following introductory text is added after the title 'INFORMATION ON 
EXPOSURE FOR SUBSTANCES REGISTERED IN QUANTITIES BETWEEN 1 AND 10 
TONNES PER YEAR PER MANUFACTURER OR IMPORTER':  
"Where a substance being registered is manufactured or imported in one or several 
nanoforms, the information pursuant to this Section shall address the different 
nanoforms or sets of similar nanoforms as characterised in subsection 2.4 
separately. " 
 11 
 4. Annex  VII to Regulati on (EC) No 1907/2006 is amended as follows:  
 
(a) "In the introductory text, the following text is added after the third paragraph:  
"Without prejudice to the information submitted for other forms, any relevant 
physicochemical, toxicological and ecotoxicolo gical information shall include 
characterisation of the nanoform tested and test conditions. Where QSARs are used 
or evidence is obtained by means other than testing, a description shall be provided 
of the range of material characteristics/properties to wh ich the evidence can be 
applied. ";  
(b) Subsection 7.7 is replaced by the following:  
7.7. Water solubility  7.7. The study does not need to be conducted where : 
– the substance is hydrolytically unstable at pH 4, 7 and 9 
(half -life less than 12 hours), or  
–            the substance is readily oxidisable in water.  
Where  the substance appears ‘insoluble’ in water, a limit test up to 
the detection limit of the analytical method shall be performed.  
For nanoforms the potential confounding effect of dispersion shall  be 
assessed when conducting the study.  
(c) Subsection 7.8 is replaced by the following:  
7.8. Partition 
coefficient n -
octanol/water  7.8. The study does not need to be conducted if the substance is 
inorganic. If the test cannot be performed (e.g. the substance 
decomposes, has a high surface activity, reacts violently during the 
performance of the test or does not dissolve in water or in octanol, or 
it is not possible to obtain a sufficiently pure substance), a calculated 
value for log P as well as deta ils of the calculation method shall be 
provided.]  
For nanoforms the potential confounding effect of dispersion in 
octanol and water shall be assessed.  
(d) After subsection 7.14., the following  is added:  
7.14 bis Dustiness  
Only f or nanoforms  7.14 bis. The study does not need to be conducted if exposure to 
granular form of the substance during its life -cycle can be excluded.  
(e) Point 8.4.1. is replaced by the following:  
8.4.1. In vitro gene 
mutation study in 
bacteria  8.4.1. The study does not need to be conducted if it is not appropriate 
for some nanoforms. In such case other studies involving one or 
more in vitro mutagenicity study(ies) in mammalian cells (Annex 
VIII, sections 8.4.2. and 8.4.3 or other internationally recognised 
methods) shall be prov ided.   12 
 (f) Point 8.5.1 is replaced by the following:  
8.5.1. By oral route  8.5.1. The study need not be conducted if 
a study on acute toxicity by the inhalation route (8.5.2) is available.  
For nanoforms, if any of the routes in Annex VIII 8.5.2 or 8.5.3 is the 
more appropriate route of exposure that study may be conducted 
instead.  
(g) Point 9.1.1. is replaced by the following:  
9.1.1. Short -term 
toxicity testing on 
invertebrates 
(preferred species 
Daphnia)  
The registrant may 
consider long -term 
toxicity te sting 
instead of short -term.  9.1.1. The study does not need to be conducted if:  
- there are mitigating factors indicating that aquatic toxicity is 
unlikely to occur for instance if the substance is highly 
insoluble in water or the substance is unlikely to cross 
biological membranes . Moreover, for nanoforms high 
insolubility in water alone cannot serve as justification for 
waiving the test ;   
- a long -term aquatic toxicity study on invertebrates is 
available, or  
- adequate information for environmental class ification and 
labelling is available.  
The long -term aquatic toxicity study on Daphnia  (Annex IX, section 
9.1.5.) shall be considered if the substance is poorly water soluble . 
(h) Point 9.1.2. is replaced by the following:  
9.1.2. Growth 
inhibition study 
aquatic plants (algae 
preferred)  9.1.2. The study does not need to be conducted if there are mitigating 
factors indicating that aquatic toxicity is unlikely to occur for 
instance if the substance is highly insoluble in water or the substance 
is unlikely to  cross biological membranes . Moreover, for nanoforms 
high insolubility in water alone cannot serve as justification for 
waiving the test.    
 13 
 5. Annex  VIII to Regulation (EC) No 1907/2006 is amended as follows:  
 
(a) "In the introductory text, the following text is added after the first paragraph:  
"Without prejudice to the information submitted for other forms, any relevant 
physicochemical, toxicological and ecotoxicological information shall include 
characterisation o f the nanoform tested and test conditions. Where QSARs are used 
or evidence is obtained by means other than testing, a description shall be provided 
of the range of material characteristics/properties to which the evidence can be 
applied. ";  
(b) Subsection  8.5. is replaced by the following:  
8.5. Acute toxicity  
 
 
 
 
 8.5. The study/ies do(es) not generally need to be conducted if:  
- the substance is classified as corrosive to the skin.  
In addition to the oral route (8.5.1.) or to the more appropriate route 
as indicated in Annex VII for nanoforms, for substances other than 
gases, the information mentioned under 8.5.1. to 8.5.3. shall be 
provided for at least one other route. The choice for the second route 
will depend on the nature of the substance and the lik ely route of 
human exposure. If there is only one route of exposure, information 
for only that route need be provided.  
(c) Point 8.6.1 is replaced by the following:  
8.6.1. Short -term 
repeated dose toxicity 
study (28 days), one 
species, male and 
female, most 
appropriate route of 
administration, having 
regard to the likely 
route of human 
exposure.  8.6.1. The short -term toxicity study (28 days) does not need to be 
conducted if:  
- a reliable sub -chronic (90 days) or chronic toxicity study is 
available, provi ded that an appropriate species, dosage, 
solvent and route of administration were used, or  
- where a substance undergoes immediate disintegration and 
there are sufficient data on the cleavage products, or  
- relevant human exposure can be excluded in accord ance 
with Annex XI Section 3.  
The appropriate route shall be chosen on the following basis:  
Testing by the dermal route is appropriate if:  
– inhalation of the substance is unlikely; and  
– skin contact in production and/or use is likely; and  
– the physicoch emical and toxicological properties 
suggest potential for a significant rate of absorption 
through the skin.  
Testing by the inhalation route is appropriate if exposure of humans 
via inhalation is likely taking into account the vapour pressure of the 
substa nce and/or the possibility of exposure to aerosols, particles or 14 
 droplets of an inhalable size.  
For nanoforms a histopathological determination of brain and lung 
tissues, as well as an examination of relevant parameters in 
bronchoalveolar lavage (BAL) flui d, kinetics, where relevant, and 
recovery period shall be considered when conducting the test, taking 
into account the relevant technical guidance at the international level.  
The sub -chronic toxicity study (90 days) (Annex IX, Section 8.6.2) 
shall be proposed by the registrant if: the frequency and duration of 
human exposure indicates that a longer term study is appropriate;  
and one of the following conditions is met:  
- other available data indicate that the substance may have a 
dangerous property that  cannot be detected in a short -term 
toxicity study, or  
- appropriately designed toxicokinetic studies reveal 
accumulation of the substance or its metabolites in certain 
tissues or organs which would possibly remain undetected in 
a short -term toxicity study  but which are liable to result in 
adverse effects after prolonged exposure.  
Further studies shall be proposed by the registrant or may be required 
by the Agency in accordance with Article 40 or 41 in case of:  
- failure to identify a NOAEL in the 28 or the  90 days study, 
unless the reason for the failure to identify a NOAEL is 
absence of adverse toxic effects, or  
- toxicity of particular concern (e.g. serious/severe effects), or  
- indications of an effect for which the available evidence is 
inadequate for t oxicological and/or risk characterisation. In 
such cases it may also be more appropriate to perform 
specific toxicological studies that are designed to investigate 
these effects (e.g. immunotoxicity, neurotoxicity, and for 
nanoforms - indirect genotoxicity  as a result of persistent 
inflammation), or  
- the route of exposure used in the initial repeated dose study 
was inappropriate in relation to the expected route of human 
exposure and route -to-route extrapolation cannot be made, 
or 
- particular concern rega rding exposure (e.g. use in consumer 
products leading to exposure levels which are close to the 
dose levels at which toxicity to humans may be expected), 
or 
- effects shown in substances with a clear relationship in 
molecular structure with the substance b eing studied, were 
not detected in the 28 or the 90 days study.  
 15 
 (d) Subsection 8.8. is replaced by the following:  
8.8. Toxicokinetics   
8.8.1. Assessment of 
the toxicokinetic 
behaviour of the 
substance to the 
extent that can be 
derived from the 
relevant available 
information.  For nanoforms a toxicokinetics study shall be proposed or may be 
required by the Agency in accordance with Article 40 or 41 in case 
such an assessment cannot be performed on the basis of the relevant 
available information, i ncluding from the study conducted in 
accordance with 8.6.1.  
The choice of the study will depend on the remaining information 
gaps and the results of the chemical safety assessment . 
(e) Point 9.1.3 is replaced by the following:  
9.1.3. Short -term 
toxicity testing on 
fish: the registrant 
may consider long -
term toxicity testing 
instead of short -term.  9.1.3. The study does not need to be conducted if:  
- there are mitigating factors indicating that aquatic toxicity is 
unlikely to occur, for instance the substan ce is highly 
insoluble in water or the substance is unlikely to cross 
biological membranes, or  
- a long -term aquatic toxicity study on fish is available.  
For nanoforms high insolubility in water alone cannot serve as an 
indication that aquatic toxicity is unlikely to occur.  
Long -term aquatic toxicity testing as described in Annex IX shall be 
considered if the chemical safety assessment according to Annex I 
indicates the need to investigate further effects on aquatic organisms. 
The choice of the appropriate  test(s) will depend on the results of the 
chemical safety assessment.  
The long -term aquatic toxicity study on fish (Annex IX, Section 
9.1.6) shall be considered if the substance is poorly water soluble.  
(f) Point 9.1.4. is replaced by the following:  
9.1.4. Activated 
sludge respiration 
inhibition testing  9.1.4. The study does not need to be conducted if:  
- there is no emission to a sewage treatment plant, or  
- there are mitigating factors indicating that microbial toxicity 
is unlikely to occur, for instance the substance is highly 
insoluble in water, or  
- the substance is found to be readily biodegradable and the 
applied test concentrations are in the range of concentrations 
that can be expected in the influent of a sewage treatment 
plant.  
For nanofo rms high insolubility in water alone cannot serve as an 
indication that microbial toxicity is unlikely to occur.  
The study may be replaced by a nitrification inhibition test if 16 
 available data show that the substance is likely to be an inhibitor of 
microbia l growth or function, in particular nitrifying bacteria.  
(g) Subsection 9.2. is replaced by the following:  
9.2. Degradation  
 
 
 
 9.2. Further degradation testing shall be considered if the chemical 
safety assessment according to Annex I indicates the need  to 
investigate further the degradation of the substance. For nanoforms 
such test(s) shall consider morphological transformation (e.g. 
irreversible changes in particle size, shape and surface properties, 
loss of coating), chemical transformation (e.g. oxid ation, reduction) 
and other abiotic degradation (e.g. photolysis). The choice of the 
appropriate test(s) will depend on the results of the chemical safety 
assessment.  
(h) Section 9.2.2 is replaced by the following:  
9.2.2. Abiotic  
9.2.2.1. Hydrolysis as 
a function of pH.  9.2.2.1. The study does not need to be conducted if:  
- the substance is readily biodegradable, or  
- the substance is highly insoluble in water.  
For nanoforms high insolubility in water alone cannot serve as a 
justification for waiving.  
(i) Point 9.3.1. is replaced by the following:  
9.3.1. 
Adsorption/desorption 
screening  
 9.3.1. The study does not need to be conducted if:  
- based on the physicochemical properties the substance can 
be expected to have a low potential for adsorption (e.g. the  
substance has a low octanol -water partition coefficient), or  
- the substance and its relevant degradation products 
decompose rapidly.  
For nanoforms, the Octanol -Water Partition Coefficient (Kow) or 
Soil Adsorption Coefficient (Koc/Kd) parameters shall only be used 
in the waiving with an adequate justification of their relevance for the 
adsorption potential of the nanoforms covered.  
 
 17 
   
6. Annex  IX to Regulation (EC) No 1907/2006 is amended as follows:  
 
(a) "In the introductory text, the following text is added after the second paragraph:  
"Without prejudice to the information submitted for other forms, any relevant 
physicochemical, toxicological and ecotoxicological information shall include 
characterisation of the nanoform tested and test conditions. Where QSARs are used 
or evidence is obtained by means other than testing, a description shall be provided 
of the range of material characteristics/properties to which the evidence can be 
applied. "; 
(b) After subs ection 7.17, the following is added:  
7.18. Further 
information on 
physicochemical 
properties  
Only f or nanoforms  Further testing for nanoforms covered by the registration shall be 
considered by the registrant or may be required by the Agency in 
accordance  with Article 41, if there is an indication that specific 
additional particle properties significantly influence hazard of or 
exposure to those nanoforms and only if these are relevant in 
toxicological, ecotoxicological or risk characterisation.  
 
(c) Point 8.6.2  is replaced by the following:  
8.6.2. Sub -chronic 
toxicity study (90 -
day), one species,  
rodent, male and 
female, most 
appropriate route of  
administration, having 
regard to the likely 
route of  
human exposure.  8.6.2. The sub -chronic toxicity study (9 0 days) does not need to be 
conducted if:  
–  a reliable short -term toxicity study (28 days) is available 
showing severe toxicity effects according to the criteria for 
classifying the substance as R48, for which the observed 
NOAEL -28 days, with the applicat ion of an appropriate 
uncertainty factor, allows the extrapolation towards the 
NOAEL -90 days for the same route of exposure; or  
–  a reliable chronic toxicity study is available, provided that 
an appropriate species and route of administration were 
used; o r 
–  a substance undergoes immediate disintegration and there 
are sufficient data on the cleavage products (both for 
systemic effects and effects at the site of uptake); or  
–  the substance is unreactive, insoluble and not inhalable and 
there is no evidenc e of absorption and no evidence of 
toxicity in a 28 -day "limit test", particularly if such a pattern 
is coupled with limited human exposure.  
The appropriate route shall be chosen on the following basis:  
Testing by the dermal route is appropriate if:  
(1) skin contact in production and/or use is likely; and  18 
 (2) the physicochemical properties suggest a significant rate of 
absorption through the skin; and  
(3) one of the following conditions is met:  
–  toxicity is observed in the acute dermal toxicity test at lower 
doses than in the oral toxicity test; or  
–  systemic effects or other evidence of absorption is observed in 
skin and/or eye irritation studies; or  
–  in vitro tests indicate significant dermal absorption; or  
–  significant dermal toxicity or dermal p enetration is recognised 
for structurally -related substances.  
Testing by the inhalation route is appropriate if:  
–  exposure of humans via inhalation is likely taking into 
account the vapour pressure of the substance and/or the 
possibility of exposure to a erosols, particles or droplets of an 
inhalable size.  
For nanoforms a histopathological determination of brain and lung 
tissues, as well as an examination of relevant parameters in 
bronchoalveolar lavage (BAL) fluid, kinetics, where relevant, and 
recovery p eriod shall be considered when conducting the test, taking 
into account the relevant technical guidance at the international level.  
Further studies shall be proposed by the registrant or may be required 
by the Agency in accordance with Articles 40 or 41 i n case of:  
–  failure to identify a NOAEL in the 90 days study unless the 
reason for the failure to identify a NOAEL is absence of 
adverse toxic effects; or  
–  toxicity of particular concern (e.g. serious/severe effects); or  
–  indications of an effect for  which the available evidence is 
inadequate for toxicological and/or risk characterisation. In 
such cases it may also be more appropriate to perform specific 
toxicological studies that are designed to investigate these 
effects  (e.g. immunotoxicity, neuroto xicity, and for 
nanoforms - indirect genotoxicity as a result of persistent 
inflammation), or  
–  particular concern regarding exposure (e.g. use in consumer 
products leading to exposure levels which are close to the 
dose levels at which toxicity to humans may be expected).  
 
 
(d) Point 9.2.1.2. is replaced by the following:  
9.2.1.2. Simulation 
testing on ultimate 9.2.1.2. The study need not be conducted if :  19 
 degradation in surface 
water  the substances is highly insoluble in water, or  
the substance is readily biodegradable.  
For nanoforms high insolubility in water alone cannot serve as a 
justification for waiving.   
(e) Subsection 9.3. is replaced by the following:  
9.3. Fate and 
behaviour in the 
environment   
9.3.2. 
Bioaccumulation in 
aquatic species,  
preferably fish  
 9.3.2. The study need not be conducted if:  
the substance has a low potential for bioaccumulation (for instance a 
log Kow ≤ 3) and/or a low potential to cross biological 
membranes, or  
direct and indirect exposure of the aquatic compartment  is unlikely.  
For nanoforms, the Octanol -Water Partition Coefficient (Kow) or 
Soil Adsorption Coefficient (Koc/Kd) parameters shall not be used 
without adequate justification for waiving based on the low potential 
for bioaccumulation or the unlikely direct  and indirect exposure of 
the aquatic compartment .  
9.3.3. Further 
information on 
adsorption/desorption 
depending on the 
results of the study 
required in Annex 
VIII 9.3.3. The study need not be conducted if:  
based on the physicochemical properties, can be  expected to have a 
low potential for adsorption, or  
the substance and its degradation products decompose rapidly.  
For nanoforms, the physicochemical properties shall not be used 
without adequate justification for waiving based on the low potential 
for ads orption.  
(f) Subsection 9.4 is replaced by the following:  
9.4. Effects on 
terrestrial organisms  
 
 
 
 
 
 
 9.4. These studies do not need to be conducted if direct and indirect 
exposure of the soil compartment is unlikely.  
In the absence of toxicity data for  soil organisms, the equilibrium 
partitioning method may be applied to assess the hazard to soil 
organisms. If applying the equilibrium partitioning method to 
nanoforms covered by the registration, this shall be scientifically 
justified.   
The choice of the  appropriate tests depends on the outcome of the 
chemical safety assessment.  
In particular for substances that have a high potential to adsorb to soil 
(e.g. some nanoforms) or that are very persistent, the registrant shall 
consider long -term toxicity testi ng instead of short -term.  20 
  
  21 
 7. Annex  X to Regulation (EC) No 1907/2006 is amended as follows:  
 
(a) "In the introductory text, the following text is added after the second paragraph:  
Without prejudice to the information submitted for other forms, any relevant 
physicochemical, toxicological and ecotoxicological information shall include 
characterisation of the nanoform tested and test conditions. Where QSARs are used 
or evidence is obtained by means other than testing, a description shall be provided 
of the range of material characteristics/properties to which the evidence can be 
applied. ";  
(b) Point 8.6.3. is replaced by the following:  
  8.6.3. A long -term repeated toxicity study (≥ 12 months) may be 
proposed by the registrant or required by the Agenc y in accordance 
with Articles 40 or 41 if the frequency and duration of human 
exposure indicates that a longer term study is appropriate and one of 
the following conditions is met:  
- serious or severe toxicity effects of particular concern were 
observed in  the 28 -day or 90 -day study for which the 
available evidence is inadequate for toxicological evaluation 
or risk characterisation, or  
- effects shown in substances with a clear relationship in 
molecular structure with the substance being studied were 
not de tected in the 28 -day or 90 -day study, or  
- the substance may have a dangerous property that cannot be 
detected in a 90 -day study.  
If nanoforms are covered by the registration, physicochemical 
characteristics as well as molecular structure shall be taken into 
consideration when determining if one of the conditions above are 
met.   
 
 22 
 8. Annex  XI to Regulation (EC) No 1907/2006 is amended as follows:  
 
(a) "In the introductory text, the following text is added after the last paragraph:  
The requirements specific to nanoforms in this Annex are without prejudice to 
requirements applicable to other forms of a substance. "; 
(b) Point 1.1.3. is replaced by the following:  
"1.1.3. Historical human data  
Historical human data, such as epidemiologi cal studies on exposed populations, 
accidental or occupational exposure data and clinical studies, shall be considered.  
The strength of the data for a specific human health effect depends, among other 
things, on the type of analysis and on the parameters c overed and on the magnitude 
and specificity of the response and consequently the predictability of the effect. 
Criteria for assessing the adequacy of the data include:  
(1) – the proper selection and characterisation of the exposed and control groups;  
(2) –adequate  characterisation of exposure ;  
(3) – sufficient length of follow -up for disease occurrence;  
(4) –valid method for observing an effect;  
(5) –proper consideration of bias and confounding factors; and  
(6) – a reasonable statistical reliability to justify the conclusion.  
In all cases adequate and reliable documentation shall be provided.  
When nanoforms are covered by the registration the above approach shall address the 
nanoforms separately. ";  
(c) Subsection 1.2. is replaced by the following :  
"1.2. Weight of evidence  
There may be sufficient weight of evidence from several independent sources of 
information leading to the assumption/conclusion that a substance has or has not a 
particular dangerous property, while the information from each single source alone is 
regarded insuf ficient to support this notion.  
There may be sufficient weight of evidence from the use of newly developed test 
methods, not yet included in the test methods referred to in Article 13(3) or from an 
international test method recognised by the Commission or the Agency as being 
equivalent, leading to the conclusion that a substance has or has not a particular 
dangerous property.  
Where sufficient weight of evidence for the presence or absence of a particular 
dangerous property is available:  
further testing on v ertebrate animals for that property shall be omitted,  
further testing not involving vertebrate animals may be omitted.  23 
 In all cases adequate and reliable documentation shall be provided.  
When nanoforms are covered by the registration the above approach sha ll address the 
nanoforms separately. "; 
(d) Subsection 1.3. is replaced by the following:  
"1.3. Qualitative or Quantitative structure -activity relationship ((Q)SAR)  
Results obtained from valid qualitative or quantitative structure -activity relationship 
models ((Q)SARs) may indicate the presence or absence of a certain dangerous 
property. Results of (Q)SARs may be used instead of testing when the following 
conditions are met:  
-– results are derived from a (Q)SAR model whose scientific validity has been 
estab lished,  
– the substance falls within the applicability domain of the (Q)SAR model,  
– results are adequate for the purpose of classification and labelling and/or risk 
assessment, and  
– adequate and reliable documentation of the applied method is provided.  
The Agency in collaboration with the Commission, Member States and interested 
parties shall develop and provide guidance in assessing which (Q)SARs will meet 
these conditions and provide examples.  
When nanoforms are covered by the registration the above ap proach shall address the 
nanoforms separately. "; 
(e) The last paragraph in Section 1.4 is  replaced by the following:  
"Such confirmation may be waived if the following conditions are met:  
(1) results are derived from an in vitro  method whose scientific validit y has 
been established by a validation study, according to internationally 
agreed validation principles;  
(2) results are adequate for the purpose of classification and labelling and/or 
risk assessment; and  
(3) adequate and reliable documentation of the applied met hod is provided.  
When nanoforms are covered by the registration the above approach in Points 
(1) to (3) shall address the nanoforms separately. "; 
  24 
 (f) The first paragraph in Section 1.5 is replaced by the following:  
"Substances whose physicochemical, toxicological and eco -toxicological properties 
are likely to be similar or follow a regular pattern as a result of structural similarity 
may be considered as a group, or ‘category’ of substances. Application of the group 
concept requires that physicochemic al properties, human health effects and 
environmental effects or environmental fate may be predicted from data for reference 
substance(s) within the group by interpolation to other substances in the group (read -
across approach). This avoids the need to tes t every substance for every endpoint. 
The Agency, after consulting with relevant stakeholders and other interested parties, 
shall issue guidance on technically and scientifically justified methodology for the 
grouping of substances sufficiently in advance of the first registration deadline for 
phase -in substances.  
When nanoforms are covered by the registration the above approach shall address the 
nanoforms separately. For grouping different nanoforms of the same substance the 
molecular structural similariti es alone cannot serve as a justification.  
If nanoforms covered by a registration are grouped or placed in a ‘category’ with 
other forms, including other nanoforms, of the substance in the same registration the 
obligations above shall apply in the same mann er." 
  25 
 9. Annex  XII to Regulation (EC) No 1907/2006 is amended as follows:  
 
(a) The introductory text is replaced by the following:  
"INTRODUCTION  
The purpose of this Annex is to set out how downstream users are to assess and 
document that the risks arising from the substance(s) they use are adequately 
controlled during their use for a use not covered by the Safety Data Sheet supplied to 
them and that other users further down the supply chain can adequately control the 
risks. The assessment shall cove r the life -cycle of the substance, from its receipt by 
the downstream user, for his own uses and for his identified uses further down the 
supply chain. The assessment shall consider the use of the substance on its own, in a 
mixture or in an article.  
The as sessment shall address nanoforms when they are covered by the registration. 
Justifications and conclusions drawn from the assessment shall be relevant to the 
nanoforms.  
In carrying out the chemical safety assessment and producing the Chemical Safety 
Repor t, the downstream user shall take account of information received from the 
supplier of the chemical in accordance with Article 31 and 32 of this Regulation.  
When nanoforms of the substance are covered by his own use or identified uses 
down the supply chai n, an appropriate metric for the assessment and presentation of 
the results in steps 1 -6 of the chemical safety assessment under 0.6.1 and 0.6.2 shall 
be considered, with the justification included in the chemical safety report and 
summarised in the safety  data sheet. A multiple metric presentation is preferable, 
ensuring availability of mass metric information.  
Where available and appropriate, an assessment carried out under Community 
legislation, (e.g. risk assessments completed under Regulation (EEC) No 793/93) 
shall be taken into account in the chemical safety assessment and be reflected in the 
Chemical Safety Report. Deviations from such assessments shall be justified. 
Assessments carried out under other international and national programmes may also 
be taken into account.  
The process which the downstream user goes through in carrying out the chemical 
safety assessment and in producing his Chemical Safety Report, involves three 
steps: "; 
(b) Under Step 2, the following text is added after the first paragr aph:  
"When nanoforms of the substance are covered by his own use or identified uses 
down the supply chain, the assessment shall cover the hazard, PBT and vPvB 
assessment of nanoforms(s) as used. ";  26 
 (c) Under Step 2, the third paragraph is replaced by the following:  
"In those  cases where the downstream user considers that information , in addition to 
that provided by the supplier , is necessary for producing his Chemical Safety Report , 
the downstream user shall gather this information. Wher e this information can only 
be obtained by testing on vertebrate animals, he shall submit a proposal for a testing 
strategy to the Agency in accordance with Article 38. He shall explain why he 
considers that additional information is necessary. While waiti ng for results of 
further testing, he shall record in his chemical safety report the risk management 
measures intended to manage the risks being explored that he has put in place. The 
above record taking shall address nanoforms when they are covered by his own uses  
or identified uses down the supply chain. Such information shall be relevant to the 
nanoforms. "