ANNEX 2 TO FINAL REPORT - European Commission€¦ · Annex 2 to Final Report - Case Studies of Option Scenario Examination and assessment of consequences for industry, consumers,

European Commission, Joint Research Centre –

Institute for Health and Consumer Protection – Ispra/Italy

Examination and assessment of consequences for industry, consumers, human health and the environment of possible options for changing the REACH

requirements for nanomaterials

REFERENCE: IHCP/2011/I/05/27/OC

ANNEX 2 TO FINAL REPORT

CASE STUDIES OF OPTION SCENARIO

09 January 2013

in cooperation with

BiPRO

Beratungsgesellschaft für integrierte Problemlösungen

IHCP/2011/I/05/27/OC – Annex 2 ii

European Commission

Annex 2 to Final Report - Case Studies of Option Scenario Examination and assessment of consequences for industry, consumers, human health and the environment of possible options for changing the REACH requirements for nanomaterials

Content

1 Overview on content of Annex 2 and brief summary of applied cost assessment ................... 4

2 Brief description of methodology of assessment of testing costs ........................................... 5

3 Case study for nano titanium dioxide (TiO2) .......................................................................... 6

Option 6: Include information on dustiness (substance identification and physico-chemical

properties) .................................................................................................................. 6

Option 11: Require acute toxicity data for the most relevant route of exposure ........................ 7

Option 12: Change "particles" to "nanoparticles" for repeated dose toxicity studies

(inhalation) (human health hazards) .......................................................................... 8

Option 13: Require non-bacterial in vitro gene mutation study (human health hazards) ........... 9

Option 16: Consider water solubility in relation to test waiving (environmental fate and

hazards) .................................................................................................................... 10

Option 17: Specify that long term testing should not be waived based on lack of short term

toxicity (environmental fate and hazards)................................................................ 13

Option 18: Specify that algae testing should not be waived based on insolubility

(environmental fate and hazards) ............................................................................ 14

Option 19: Require that testing on soil and sediment organisms is prioritized (environmental

fate and hazards) ...................................................................................................... 15

Option 21: Require considerations of most appropriate/relevant metric with preferable

presentation in several metrics (exposure assessment and risk characterisation) .. 17

4 Case study for nano zinc oxide (ZnO) .................................................................................. 18

Option 6: Include information on dustiness ............................................................................... 18

Option 11: Require acute toxicity data for the most relevant route of exposure (Annex VII) ... 19


(inhalation)................................................................................................................ 20

Option 13: Require non-bacterial in vitro gene mutation study ................................................. 21

Option 16: Consider water solubility in relation to test waiving ................................................ 22


toxicity ...................................................................................................................... 25

Option 18: Specify that algae testing should not be waived based on insolubility .................... 27

Option 19: Require that testing on soil and sediment organisms is prioritized ......................... 27



5 Case study for nano diamond ............................................................................................. 29

Option 6: Include information on dustiness ............................................................................... 29

Option 11: Require acute toxicity data for the most relevant route of exposure (Annex VII) ... 29

Option 12: Change „particles“ to „(nano)particles“ for repeated dose toxicity studies

(inhalation)................................................................................................................ 30

Option 13: Require non-bacterial in vitro gene mutation study ................................................. 31

Option 16: Consider water solubility in relation to test waiving ................................................ 32

IHCP/2011/I/05/27/OC – Annex 2 iii

European Commission



toxicity ...................................................................................................................... 33

Option 18: Specify that algae testing should not be waived based on insolubility .................... 34

Option 19: Require that testing on soil and sediment organisms is prioritized ......................... 35



IHCP/2011/I/05/27/OC – Annex 2 4

European Commission


1 Overview on content of Annex 2 and brief summary of applied

cost assessment

This Annex 2 to the Final Report (Case studies of option scenario) describes the estimations of

registration costs for industry and the underlying assumptions due to the options attributed to the

option scenario, as summarised in Table A2-1at the end of this Annex.

The aspect of size being considered as characteriser or identifier has a great impact on the

registration obligation and consequently on the testing costs. Considering size as characteriser would

result in elaboration of an updated lead dossier, in which information on one (or several) nanoforms

would be included. As already explained in the main report the information requirements for the

lead dossier would be triggered by the allocated tonnages of the bulk form and the nanoform.

On the contrary, considering size as an identifier would lead to elaboration of a separate lead dossier

for nanomaterials. Especially with regard to surface treated nanomaterials no exact advice/guidance

is available how to register these nanomaterials. These aspects have already been discussed

extensively in the main report and will not be repeated at this stage. Based on these uncertainties

the project team has elaborated two sub-options for each identified option by assessing the costs for

a possible dossier update and costs for elaboration of a separate lead dossier for nanomaterials.

The exact provisions and information requirements have already been discussed in detail in Annex 1

to this report and will therefore not be repeated again.

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European Commission


2 Brief description of methodology of assessment of testing

costs

A key topic within this project is the assessment of possible costs which may occur after

implementation of the options (baseline and option scenario).

For the calculation of probable testing costs the project team used pricing lists of laboratories with

which the project team has been provided in recent years. Since the project team has also launched

testings in recent months on behalf of its clients a good overview on current laboratory costs can be

given. In order to review whether the offered service costs were also in the same range as for

nanomaterials, an inquiry with two German laboratories has been performed which revealed quite

contradictionary statements. One laboratory has not adopted its pricing policy on testing of

nanomaterials, resulting in the same testing costs for nanomaterials and substances in bulk form.

According to the laboratory´s responsible person there were rare cases where higher testing costs

occurred, but these were results of additional efforts during the performing of tests with

nanomaterials on which the customer explicitly has insisted prior to the start of the test.

The second laboratory stated that principally testing costs for nanomaterials were higher than testing

with the corresponding bulk form. Referring to the laboratory´s responsible person higher testing

costs were considered as a result of higher efforts with regard to analytical monitoring/

determination of nanomaterials. It has furthermore been explicitly stated that no clear picture of

testing costs for nanomaterials can be provided since the occurring higher testing costs were case-to-

case-based and therefore no common pricing policy could been provided.

These two inquiry results demonstrate quite clearly that – since no standard operating procedures

for testing of nanomaterials have been developed – no uniform pricing policy among the laboratories

can be given.

The inconsistent pricing of testings for nanomaterials might also be the reason why the European

Commission recently has invited for a tender ("Implementing TMR: Test house capacities for testing")

in which also current testing and pricing of nanomaterials are subjected to the requirements of the

tender.

In order to assess resulting testing costs quite accurately the project team decided on using the

current laboratory´s prices as the lower limit and prices which are based on a paper1 as a higher

limit.

1 "Testing Costs and Testing Capacity According to the REACH Requirements – Results of a Survey of Independent and

Corporate GLP Laboratories in the EU and Switzerland"; M. Fleischer; Journal of Business Chemistry; 2007; Vol. 4, pp. 96

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European Commission


3 Case study for nano titanium dioxide (TiO2)

The current lead dossier for TiO2 includes information on various forms of this substance: the bulk

form of TiO2, nano TiO2, silanised TiO2 (e.g. TiO2 805) and alumina/silica coated sub-pigmentary TiO2.

Due to reasons of simplification the project team will focus on nano TiO2 and its silanised form for

the further cost assessment.

Depending on synthesis methods or manufacturing processes, nano TiO2 can crystallize in different

morphologies or shapes.

Not only the shape but also the surface of nano TiO2 can be functionalized according to the

subsequent intended application, e.g. by treating the nanomaterial with a silane. As already indicated

above, surface treated TiO2 (e.g. silanised TiO2) has partly been assessed in the scope of the

registration process.

Option 6: Include information on dustiness (substance identification and physico-chemical

properties)

Size as characteriser:

Additional costs for carrying out tests on dustiness would occur in the case of an update of the

already submitted lead dossier. Referring to the outcomes of the RIP-oN2 report, measurements on

the dustiness of nanomaterials can be performed by carrying out the rotating drum method (EN

15051) and the continuous drop method (EN 15051). These methods are also suggested in the ECHA

"Guidance on information requirements and chemical safety assessment – Chapter R-7a: Endpoint

specific guidance" and would lead to costs of approximately 600 €. However, studies which have

been performed in the course of the NanoCare project revealed a necessity for an adaption of the

current testing methods in order to characterise nanomaterials more appropriately. Taking into

account that a modification of a current testing method would lead to additional costs of

approximately 500 €, the performing of additional two tests on dustiness would result in total testing

costs of 2,200 €. The elaboration of the corresponding IUCLID endpoint and the endpoint summary

would result in additional costs of 500 € (equivalent to a half working day per test).

Additional costs would occur if further nanoforms of TiO2 would be covered by the lead dossier for

which it might be regarded that testing on dustiness is required (e.g. nano TiO2 with smaller particle

size than the one with which the test has been conducted).

Additional costs: 2,700 €

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Size as identifier:

The aforementioned calculated costs would also have to be settled by the registrant in the course of

preparing a separate lead dossier for nano TiO2.


Option 11: Require acute toxicity data for the most relevant route of exposure


The lead dossier of TiO2 includes information on various forms of TiO2: the bulk form of TiO2, nano

TiO2 silanised TiO2 (e.g. TiO2 805) and alumina/silica coated sub-pigmentary TiO2. Due to reasons of

simplification the project team will focus only on nano TiO2 and its silanised form for the further cost

assessment.

Oral and inhalative exposure are regarded to be the two main exposure routes for TiO2 – the hazard

assessment for these two exposure routes has consequently been considered and performed via

short-term and long-term tests.

The TDIC (Titanium Dioxide Industry Consortium) has indicated in its completed questionnaire that

no distinction has been made between the uses for nano TiO2 and its bulk form. In the lead dossier

information on acute inhalation toxicity has already been submitted for the bulk form and the

nanoform of TiO2, but not for the silanised nanoform. Unfortunately the project team cannot predict

whether exposure to the silanised nanoform of TiO2 might be of any relevance or whether the

nanomaterial is processed in a suspension, resulting in reduced inhalative exposure. Due to reasons

of simplification it is therefore assumed that exposure to the silanised nanoform might be of

relevance, too - consequently, the registrant would have to consider performing of an acute

inhalation toxicity test (e.g. according to OECD GD 39 (Guidance document on acute inhalation

toxicity testing)) for the silanised nanoform of TiO2. Performing of the test (8,300 € – 19,000 €), test

monitoring and completion of the IUCLID endpoint and the summary are regarded to lead to

additional costs between 9,300 € and 20,000 € for one tested nanoform (if no other non-testing

approaches, such as read-across or (Q)SAR are applicable). Additional costs would occur if

subsequent pathology/histology would have to be performed and a focus would have to be laid on

the examination of the BAL fluid. Given that pathology/histology and the examination of the BAL

fluid would require efforts of two working days (equivalent to 2,000 €), the project team assumes

furthermore that the accompanying analytical detection would incur additional costs of 1,500 €. In

summary, a possible implementation of information requirements of Option 11 in the REACH

Regulation would lead to additional costs between 12,800 € and 23,500 € per tested nanomaterial.

Additional costs: 12,800 € – 23,500 €

IHCP/2011/I/05/27/OC – Annex 2 8

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Size as identifier:

In case of elaborating a separate lead dossier for nano TiO2, also information on further nanoforms,

such as silanised nano TiO2, could be included. The implementation of the proposed requirements of

Option 11 foresees consideration of the most relevant route of exposure for information

requirements for Annex VII, 8.5 and Annex VIII. The TDIC (Titanium Dioxide REACH Consortium) has

indicated in its completed questionnaire that no distinction has been made between the uses for

nano TiO2 and its bulk form.

In the lead dossier information on the acute inhalation toxicity of nano TiO2 has already been

submitted and this information could also be used for the elaboration of a separate lead dossier. As it

has already been outlined above the project team has no indication on the most relevant route of

exposure for the silanised nanoform – therefore, due to reasons of simplification the project team

assumes that also for the silanised nanoform exposure via inhalation might be of relevance. Against

this background the same cost structure (performing of acute inhalation toxicity;

pathology/histology) would occur as for the abovementioned case (size as characteriser).



(inhalation) (human health hazards)


The current lead dossier for TiO2 includes information on various forms of TiO2: the bulk form of TiO2,

nano TiO2, silanised TiO2 (e.g. TiO2 805) and alumina/silica coated sub-pigmentary TiO2. A brief

examination of submitted information revealed that indeed nano TiO2 has been subjected to a long-

term assessment via the inhalative route. In the course of performing long-term inhalative tests

information on e.g. specific parameters in the BAL fluid and histopathology have been gathered.

Against this background it can reasonably be argued that no additional assessment for nano TiO2 is

required.

On the other hand no information on surface treated (e.g. silanised) nano TiO2 could not be found. At

this stage the project team cannot accurately state why information on surface treated nanomaterial

is missing in long-term inhalation studies – instead, the project team will rely on indications in the

completed questionnaire with regard to the uses of nanomaterials. Referring to this questionnaire

the consortium indicated that no distinctions have been made between the bulk and the nano form

of TiO2. The project team infers furthermore that exposure to surface treated nano TiO2 might be

taken into account, too.

Change of the wording in the appropriate REACH Annexes is considered to lead to no additional

efforts and costs since inhalation via exposure to a substance (nano form or bulk form) has per se to

be considered in the dossier elaboration process.

Additional costs: 0 €

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Size as identifier:

Implementation of Option 12 would affect information requirements of Annex VIII, 8.6.1 and Annex

IX, 8.6.2. Since information on long-term assessment via the inhalative route for nano TiO2 already

exists, no further tests would be required after a possible implementation of the requirements of

Option 12 in the REACH Regulation.

Besides, as it has already explained above, changing of the wording in the respective Annexes would

lead to no additional efforts, since probable exposure via inhalation (nano form or bulk form) is per

se considered to be taken into account.


Option 13: Require non-bacterial in vitro gene mutation study (human health hazards)


According to the publicly available information at the ECHA website for registered substances, a

broad range of in vitro genetic toxicity tests have been gathered in the course of the hazard

assessment of TiO2, such as in-vitro genetic toxicity tests (Ames test), in vitro mammalian cell gene

mutation assay, in vitro mammalian chromosome aberration tests, sister chromatid exchange assay

in mammalian cells or in vitro mammalian cell micronucleus test. A brief screening of the entered

testing results/test performing indicates that the gathered information refers to the bulk form of

TiO2, its nanoform and the silanised nanoform (T805). As it has been implied in the RIP-oN2 report,

the Ames test is not fully adequate for assessing the possible carcinogenic or mutagenic potential of

nanomaterials and a set of further standardised genotoxicity testing methods should be performed

instead.

An adaption of the wording of REACH Annex VII, 8.4, as suggested in the option, would not result in

additional efforts and costs for updating the lead dossier, since several non-bacterial in vitro tests

have been performed due to the obligative information requirements for substances which are

placed on the market in a volume of more than 1,000 tonnes per year.


Size as identifier:

In case of elaboration of a separate lead dossier for nano TiO2 also information on further

nanoforms, such as silanised nano TiO2, could be included.

As it has already been pointed in the abovementioned case (size as characteriser) nano TiO2 and its

silanised derivative have already been assessed via several non-bacterial in-vitro gene mutation

studies. The same information could be used in order to elaborate a separate lead dossier leading to

no additional testing costs.


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European Commission


Option 16: Consider water solubility in relation to test waiving (environmental fate and

hazards)


Based on a broad range of information on various water solubility tests which have been gathered in

the course of the elaboration of a lead dossier for TiO2, it has been concluded that TiO2 should be

regarded as "insoluble (< 0.1 mg/L)".

It is unfortunately not apparent which form of TiO2 has been subjected for water solubility testings.

Since the argument that water insolubility can per se not be applied on nanomaterials, subsequent

testings for the two nanoforms of TiO2 (nano TiO2 and e.g. silanised nano TiO2) should be taken into

account.

After screening column 2 of Annexes VII-IX for tests which can be waived due to low water solubility

of the testing substance, following tests have been identified which would be affected by this option:

- short-term toxicity on invertebrates (preferred species Daphnia) (Annex VII, 9.1.1)

- growth inhibition study aquatic plants (algae preferred) (Annex VII, 9.1.2)

- short-term toxicity on fish (Annex VIII, 9.1.3)

- activated sludge respiration inhibition testing (Annex VIII, 9.1.4)

- hydrolysis as a function of pH (Annex VIII, 9.1.4)

- simulation testing on ultimate degradation in surface waters (Annex IX, 9.2.1.2)

If no other non-testing methods are available, such as read-across, (Q)SAR or conditions for

exposure-based waiving, following testing costs would incur for each nanoform of TiO2:

Required tests according to Annexes VII-IX in REACH Testing costs (€)

Short-term toxicity on invertebrates (preferred species Daphnia) (Annex

VII, 9.1.1) (OECD 202) 3,600 – 4,900

growth inhibition study aquatic plants (algae preferred) (Annex VII,

9.1.2) (OECD 201) 3,000 – 5,841

short-term toxicity on fish (Annex VIII, 9.1.3) (OECD 203) 3,900 – 6,203

Activated sludge respiration inhibition testing (Annex VIII, 9.1.4) (OECD

209) 3,000 – 3,087

Hydrolysis as a function of pH (Annex VIII, 9.1.4) (OECD 111) 6,200 – 7,032

Simulation testing on ultimate degradation in surface waters (Annex IX,

9.2.1.2) (OECD 309) 35,000 – 56,000

Monitoring of each test, completion of IUCLID endpoints and endpoint

summaries 6,000

∑: 60,700 – 89,063

A brief screening of the submitted information via ECHA´s website for registered substances revealed

that for hydrolysis as a function of pH (OECD 111) and for the testing on degradation in surface

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waters (OECD 309) neither for the nano form of TiO2 nor for its surface treated derivate any testing

information has been provided. Instead the information requirements for this endpoint have been

fulfilled via a waiving approach.

For the remaining four tests which have been identified and listed in the abovementioned table

information has been provided for nano TiO2 but not for the surface treated nanoform.

Therefore, a testing strategy for nano TiO2 and its silanised derivative can be postulated:

Required tests according to Annexes

VII-IX in REACH Testing costs (€) Nano TiO2

Silanised nano

TiO2

Short-term toxicity on invertebrates 3,600 – 4,900 - +

growth inhibition study aquatic

plants (algae preferred) 3,000 – 5,841 - +

short-term toxicity on fish 3,900 – 6,203 - +

Activated sludge respiration

inhibition testing 3,000 – 3,087 - +

Hydrolysis as a function of pH 6,200 – 7,032 + +

Simulation testing on ultimate

degradation in surface waters 35,000 – 56,000 + +

Monitoring of each test, completion

of IUCLID endpoints and endpoint

summaries

1,000 per test

(6,000 € for six

tests)

+ +

∑: 43,200 – 65,032

60,700 – 89,063

Performing of the eight proposed tests, test monitoring and completion of the IUCLID endpoints and

summaries would lead finally to additional costs between 103,900 € and 154,095 €.


Size as identifier:

In case of elaboration of a separate lead dossier for nano TiO2 also information on further

nanoforms, such as silanised nano TiO2, could be included.

For a few of the endpoints which have been identified as being affected after a possible

implementation of the option´s requirements in the REACH Regulation information is already

available for at least nano TiO2. Therefore supplementing information would be required for the

silanised nanoform on which the project team has decided to focus for the cost assessment.

Depending on the tonnage band which would be covered by the dossier a different cost structure

would result. The project team has allocated the incurred costs in relation to the tonnage band and

in relation to already available information on nano TiO2:

Resulting additional costs if lead dossier covers only a tonnage band between 1-10 t/y (Annex VII):

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Silanised nano

TiO2






summaries

1,000 per test

(2,000 € for two

tests)

- +

∑: 0 8,600 – 12,741

Additional costs for substances manufactured or imported in quantities of one tonne or

more per year (Annex VII): 8,600 € – 12,741 €

Resulting additional costs if lead dossier covers a tonnage band between 10-100 t/y (Annex VIII):



Silanised nano

TiO2




short-term toxicity on fish 3,900 – 6,203 - +


inhibition testing 3,000 – 3,087 - +




summaries

1,000 per test + +

∑: 7,200 –

8,032

24,700 –

32,063

Additional costs for substances manufactured or imported in quantities of 10 tonnes or

more per year (Annex VIII): 31,900 € – 40,095 €

Resulting additional costs if lead dossier covers a tonnage band between 100-1000 t/y (Annex IX):

The cost structure for this case has already been elaborated above.

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more per year (Annex IX): 103,900 € – 154,095 €

Please note that the staggered cost structure, as outlined above, is just a mere presumption as the

TDIC (Titanium Dioxide Industry Consortium) has already indicated in a completed questionnaire that

an elaboration of a separate lead dossier for nano TiO2 is not envisaged.


toxicity (environmental fate and hazards)


The project team wants to point out that it is not in the scope of the report to carry out an in-depth

literature research, to perform a data-gap analysis or to propose a testing strategy for nano TiO2 or

surface treated nano TiO2. Therefore a possible result of a chemical safety assessment cannot be

predicted and it can therefore not be inferred whether long-term tests on aquatic organisms would

be required or not. In this context the project team claims that long-term tests on aquatic organisms

might be proposed by the registrant. If in the course of a dossier evaluation ECHA concludes that the

proposed testing may be the only possibility to provide information on the aquatoxic properties, the

lead registrant would have to perform tests as indicated in the table below and would supplement

the current lead dossier with the testing outcomes for nano TiO2. Following tests would be affected

after a possible implementation of the requirements of Option 17 in the REACH Regulation:

Required test according to Annexes in REACH Testing costs (€)

Long-term toxicity to aquatic invertebrates (according to OECD 211)

(Annex IX, 9.1.5)

11,000 – 18,092

Long-term testing on fish (Annex IX, 9.1.6)

Fish early-life stage (FELS) toxicity test (OECD 210) (Annex IX, 9.1.6.1)

or

Fish short-term toxicity test on embryo and sac-fry stages (Danio rerio)

(OECD 212) (Annex IX, 9.1.6.2) or fish short-term toxicity test on

embryo and sac-fry stages (Oncorhynchus mykiss) (OECD 212) (Annex

IX, 9.1.6.2)

or

Fish, juvenile growth test (OECD 215) (Annex IX, 9.1.6.3)

30,000 – 30,823

11,000– 27,413

16,000 – 21,466

Monitoring of proceeded tests / completion of IUCLID endpoints 2,000

∑: 24,000 – 50,915

A brief screening of the publicly available information of the TiO2 dossier reveals that information on

long-term toxicity to aquatic invertebrates and long-term toxicity to fish has already been submitted.

Unfortunately no specific information on nano TiO2 and/or its silanised form have been identified. In

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the case that a further assessment of the two nano forms of TiO2 is regarded to be required,

performing of the abovementioned testing regime would lead to additional costs between 24,000 €

and 50,915 € for one nanoform. Update of the current lead dossier by generating information on

long-term effects on aquatic organisms for nano TiO2 and its silanised derivative would lead to

additional costs between 48,000 € and 101,830 €.


Size as identifier:

In case of elaborating a separate lead dossier for nano TiO2 also information on aquatic toxicity of

silanised nano TiO2 could be included separately in the dossier. If the lead dossier would cover a

tonnage band of more than 100 tonnes year, the same costs would occur as in the case of a dossier

update.

However, as already indicated on several occasions the TDIC (Titanium Dioxide Industry Consortium)

has not signaled any intentions for elaboration of a separate lead dossier for nano TiO2.

Additional costs: 48,000 € – 101,830 € (only if lead dossier covers a tonnage band of more

than 100 t/y)


(environmental fate and hazards)


Based on testing results of water solubility tests which have been performed by the lead registrant,

TiO2 has been characterised as insoluble (< 0.1 mg/L). As already explained above the presence of

water insoluble properties of a substance are not applicable on nanomaterials. Consequently an

assessment of aquatic toxicity on algae would be required for the two nanoforms of TiO2.

A brief screening of the entries which have been entered by the lead registrant for the IUCLID

endpoint 6.1.5 "Toxicity to aquatic algae and cyanobacteria" reveals that the dossier already includes

information on toxicity on algae with nano TiO2, too. Consequently, an algal inhibition test would be

required for the surface treated nano TiO2 (silanised nano TiO2), if the information requirement

cannot be fulfilled via over non-testing means such as read-across or (Q)SAR. The resulting costs for

monitoring the test (e.g. according to OECD 201), completing the IUCLID endpoint 6.1.5 "Toxicity to

aquatic algae and cyanobacteria" (1 working day; 1,000 €) and performing the test (3,000 € – 5,841

€) would amount to between 4,000 € and 6,841 € per tested substance. Since performing the test on

toxicity to aquatic algae with the silanised nano TiO2 has already been identified as a required test in

Option 16 an identical performing of the test is therefore not required.


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Size as identifier:

In the case of elaborating a lead dossier for nano TiO2 in which e.g. also the silanised nanoform might

be covered, it is proposed that no additional costs would occur since performing of this test has

already been identified as a required test after a possible implementation of the requirements of

Option 16 in REACH.


Option 19: Require that testing on soil and sediment organisms is prioritized

(environmental fate and hazards)


Column 2 of REACH Annexes IX, 9.4 and X, 9.4 explicitly points out the fact that required tests do not

need to be performed if direct or indirect exposure to the affected compartment is unlikely.

Furthermore, long-term toxicity testing should be taken into account instead of short-term if the

tested substance has a high potential to adsorb to soil or is very persistent (Annex IX, 9.4). Long-term

tests should per se be proposed if the outcome of the chemical safety assessment indicates the need

for a subsequent assessment of hazardous effects.

The TDIC (Titanium Dioxide Industry Consortium) has indicated in a questionnaire that no distinctions

have been made with regard to the use for nano TiO2 and its bulk form. Instead, it has been indicated

that uses for nano TiO2 are covered by uses of pigmentary TiO2.

In the course of the assessment of ecotoxicity of TiO2 and nano TiO2, sediment and terrestrial toxicity

have been evaluated.

Since the project team has no information on emissions of nano TiO2 and silanised nano TiO2, it

assumes that emission to the soil and sediment compartment might still be of relevance. Given that

information requirements cannot be waived by a read-across approach, testing proposal of long-

term toxicity to sediment organisms (Annex X - 9.5.1; OECD 218/219; 9,200 € – 17,776 €) and testing

of effects on soil micro-organisms (Annex IX – 9.4.2; OECD 216/217; 5,850 € – 18,263 €) would result

in additional costs between 17,050 € and 38,039 € (incl. performing and monitoring of test,

completion of IUCLID endpoint and endpoint summary) per tested substance.

A brief examination of the submitted information on ecotoxicity revealed that no information on

toxicity to sediment organisms neither for nano TiO2, nor for its silanised derivative has been

submitted. In the case of testing of effects on soil micro-organisms information has indeed been

submitted for the nanoform of TiO2 but not for the silanised nanoform.

Based on the already provided information in the lead dossier, a testing strategy can be proposed as

follows:

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IX - X of REACH Testing costs (€) Nano TiO2

Silanised nano

TiO2

testing of effects on soil micro-

organisms (OECD 216/217) 5,850 – 18,263 - +

long-term toxicity to sediment

organisms (OECD 218/219) 9,200 € – 17,776 + +



summaries

1,000 per test + +

∑: 10,200 –

18,776

17,050 –

38,039

Against this background performing of the required tests would lead to additional costs between

27,250 € and 56,815 € (incl. performing and monitoring of test, completion of IUCLID endpoint and

endpoint summary).


Size as identifier:

In the case of particle size being regarded as an identifier a separate lead dossier would be

elaborated for nano TiO2 in which also information on e.g. silanised nano TiO2 might be included.

Since the project team has no information on emissions of the two nanoforms of TiO2, it assumes –

due to reasons of simplicity – that emission to the soil and sediment compartment might be of

relevance. Referring to the abovementioned findings in the lead dossier with regard to the

ecotoxicity additional costs would incur as follows:

Resulting additional costs if lead dossier covers a tonnage band between 100-1,000 t/y (Annex IX):

Required tests according to Annex IX

of REACH Testing costs (€) Nano TiO2

Silanised nano

TiO2

testing of effects on soil micro-

organisms (OECD 216/217) 5,850 – 18,263 - +



summaries

1,000 per test - +

∑: 6,850 – 19,263

Additional costs: 6,850 € – 19,263 € (if lead dossier would cover a tonnage of more than

100 t/y)

IHCP/2011/I/05/27/OC – Annex 2 17

European Commission


For the case of elaborating a lead dossier for a tonnage band of more than 1,000 t/y the

same cost structure would incur as for the case of a dossier update.

Additional costs: 27,250 € – 56,815 € (if lead dossier would cover a tonnage of more than

1,000 t/y)


presentation in several metrics (exposure assessment and risk characterisation)


With regard to the exposure assessment and risk characterisation, a re-evaluation of exposure

estimates and PNEC/DNEL would be required in order to take in account further metrics which are

considered to be more (or equally) relevant than the mass metric.

The project team assumes that additional efforts of 2 working days for each nanoform of TiO2 would

be required in order to take additional metrics into account and to update the CSR and the relevant

IUCLID endpoints. These steps would lead to total costs of 4,000 € for the two nanoforms of TiO2.


Size as identifier:

In the case of the elaboration of a separate lead dossier for nano TiO2 the same cost structure, as

explained above, would occur if the lead dossier would cover a tonnage band of more than 10 tonnes

year. According to Article 14 of the REACH Regulation – a chemical safety assessment should be

performed and a chemical safety report should be completed only for those substances which are

manufactured or imported in quantities of more than 10 tonnes per year. In this context it should be

pointed out that that the result of a questionnaire, which has been forwarded to the consortium,

reveals that there is no intention to elaborate a separate lead dossier for nano TiO2.

Additional costs: 4,000 € (if nano TiO2 is manufactured/imported in quantities of more

than 10 tonnes per year)

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4 Case study for nano zinc oxide (ZnO)

In the case of nano ZnO the substance can exhibit different crystallization properties which result in

different nanostructures and shapes, such as nanowires (or nanorods), nanobelts (nanoribbons),

comb-like nanowires array, nanoneedles arrays, and nanorings2. Furthermore, nanomaterials can be

modified on the surface in order to introduce completely new properties to the nanomaterial or to

prevent undesirable effects. ZnO nanoparticles tend to agglomerate due to their large surface area

and high surface energy. In order to counteract this tendency and at the same time to improve the

dispersion of the nanoparticles, the ZnO surface is modified by a broad range of substance classes.

Depending on the solvent (organic, aqueous) organoalkoxysilanes or polymethacrylic acids are

attached on the surface of nano ZnO for improving the desired properties3.

From the information content which is publicly accessible via ECHA´s website for registered

substances the lead dossier for ZnO includes information on various forms of ZnO: bulk form of ZnO,

nano ZnO, surface treated ZnO (triethoxycaprylylsilane-coated ZnO and dimethoxy-

diphenylsilane/triethoxy-caprylylsilane crosspolymer-coated ZnO). Due to reasons of simplification

the project team will focus its cost assessment activities on these three various nanoforms of ZnO,

irrespective of the fact whether the identified number of characterised forms in the lead dossier

might be misinterpreted.

Option 6: Include information on dustiness



already submitted lead dossier. Referring to the outcomes of the RIP-oN2 report, measurements on






current testing methods in order to characterise nanomaterials more appropriate. Taking into


approximately 500 €, the performing of additional three tests on dustiness would result in total

testing costs of 3,300 €. The elaboration of the corresponding IUCLID endpoint and the endpoint

summary would result in additional costs of 500 € (equivalent to a half working day).

The lead dossier gives no indication on the presence on various shapes in the nano ZnO sample –

therefore subsequent tests on dustiness might be required if different shapes of nano ZnO and its

surface treated derivatives would be identified and if there are indication that various shapes of a

nanomaterial can lead to different testing results.

2 J. Zhang; Y. Yang; B. Xu; F. Jiang; J. Li; J. Cryst. Growth 280 (2005) 509–515

3 E. Tang; G. Cheng; X. Ma; X. Pang; Q. Zhao; Appl. Surf. Sci. 252 (2006) 5227–5232 and literature cited therein.

IHCP/2011/I/05/27/OC – Annex 2 19

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Size as identifier:


preparing a lead dossier for nano ZnO which could also could include information on further

nanoforms, e.g. surface treated nano ZnO.


Option 11: Require acute toxicity data for the most relevant route of exposure (Annex VII)


Oral and inhalative exposure are regarded to be the two main exposure routes for (nano) ZnO – the

hazard assessment for these two exposure routes has consequently been considered and performed

via short-term and long-term tests. In fact, information on acute inhalation toxicity and acute oral

toxicity has been gathered for the bulk and the nano form of ZnO, but not on its surface treated

derivatives. The Zinc REACH Consortium has indicated in its completed questionnaire that no

distinction has been made between the uses for nano ZnO and its bulk form. Due to the fact that

information on short-term and long-term inhalative toxicity are already provided in the lead dossier,

it can be inferred that exposure via inhalation is to be taken into account also for nano ZnO and

eventually for its surfaces treated forms. Since information on acute inhalation toxicity also for nano

ZnO has been submitted, the possibility of performing the same tests with the surface treated nano

forms should be taken into account. In this context it should be pointed out that it is the project

team´s presumption that exposure via inhalation also to the surface treated nano forms of ZnO might

be of relevance, since no information on e.g. the production process for these two nanoforms (i.e.

whether they are produced as dispersion) is available. But due to reasons of simplification the project

team assumes that exposure via inhalation also to the two surface treated nano forms might be of

relevance.

Against this background the registrant would consequently have to consider performing of acute

inhalation toxicity tests (e.g. according to OECD GD 39 (Guidance document on acute inhalation

toxicity testing) for the two surface treated nanoforms of ZnO. Performing of the test (8,300 € –

19,000 €), test monitoring and completion of the IUCLID endpoint and the summary are regarded to

lead to additional costs between 18,600 € and 40,000 € for the two tested nanoforms of ZnO (if no

other non-testing approaches, such as read-across or (Q)SAR are applicable). Additional costs would

occur if subsequent pathology/histology would have to be performed and a focus would have to be

laid on the examination of the BAL fluid. Given that pathology/histology and the examination of the

BAL fluid would require efforts of two working days (equivalent to 2,000 €), the project team

assumes furthermore that the accompanying analytical detection would incur additional costs of

1.500 €. In summary, a possible implementation of information requirements of Option 11 in the

REACH Regulation would lead to additional costs between 25,600 € and 47,000 €.

IHCP/2011/I/05/27/OC – Annex 2 20

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Size as identifier:

In case of preparing a separate lead dossier for nano ZnO also information on further nanoforms,

such as silanised nano ZnO, could be included.

The Zinc REACH Consortium has indicated in its completed questionnaire that no distinction has been

made between the uses for nano ZnO and its bulk form. Referring to the argumentation, as outlined

above for the case of size being regarded as a characteriser, the project team implies that exposure

via inhalation to the two surface treated nanoforms of ZnO might be of relevance, too.

Consequently the registrant would have to consider performing of an acute inhalation toxicity test

(e.g. according to OECD GD 39 (Guidance document on acute inhalation toxicity testing) for two

nanoforms of ZnO. Performing of the test, test monitoring and completion of the IUCLID endpoint

and the summary are regarded to lead to additional cost as already outlined above (size as

characterizer).



(inhalation)


In the course of the assessment of repeated-dose toxicity, several repeated dose toxicity tests (incl.

inhalation toxicity) have been performed with substances which have been indicated to be –

amongst others – nano ZnO. However, no information on repeated-dose toxicity on inhalation has

been submitted for the two surface treated nano form of ZnO. At this stage of the project the

contractor has no detailed information on the probability of exposure to this nano forms via the

inhalation route.





Size as identifier:

Implementation of Option 12 would affect information requirements of Annex VIII, 8.6.1 and Annex

IX, 8.6.2. Since information on long-term assessment via the inhalative route for nano ZnO already

exists, no further tests would be required after a possible implementation of the requirements of

Option 12 in the REACH Regulation.

As it has already explained above it can be argued that no additional efforts and costs would incur

since exposure to substances (nano form or not) via inhalation has to be considered per se.

IHCP/2011/I/05/27/OC – Annex 2 21

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Option 13: Require non-bacterial in vitro gene mutation study


According to the publicly available information via ECHA´s website for registered substances, in-vitro

genetic toxicity tests (Ames test) with ZnO have been carried out. Two different surface treated ZnO

substances were subjected to the Ames test which resulted in both cases in negative outcomes. The

testing substances are in both cases characterised by their particle size (< 200 nm) and were

characterised by TEM analysis, which might lead to the assumption that nano ZnO substances might

have been tested.

As it has been implied in the RIP-oN2 report, the Ames test is not fully adequate for assessing the

possible carcinogenic or mutagenic potential of nanomaterials and a set of further standardised

genotoxicity testing methods should be performed instead. In the course of assessing in vitro

genotoxicity of ZnO, the lead registrant has performed various tests, including the Ames test, the in

vitro mammalian chromosome aberration test or DNA damage and repair assay (unscheduled DNA

synthesis in mammalian cells in vitro). From the submitted information on in vitro genotoxicity it is

unfortunately not apparent whether the information might also be applicable on the three

nanoforms which the project team, due to reasons of simplification, assumes being included in the

lead dossier. Due to a lack of information on non-bacterial in vitro gene mutation studies for the

three nanoforms subsequent testings (e.g. in vitro micronucleus test in mammalian cells

according to OECD 487) would have to be taken into account. Performing of the test (19,000 € –

23,000 €), test monitoring and completion of the IUCLID endpoint and the summary would result in

additional costs between 60,000 € and 72,000 € for three nanoforms of ZnO, if no other non-testing

methods (read-across, (Q)SAR) are not applicable. As explained above, the Ames test is considered as

not fully adequate for assessment of nanomaterials. Therefore, the Ames test is not further

considered in the cost calculation – instead, as outlined above, more appropriate test methods are

taken into account.


Size as identifier:



Performing of in vitro micronucleus tests in mammalian cells according to OECD 487 would result in

the same cost structure as outlined above.


IHCP/2011/I/05/27/OC – Annex 2 22

European Commission


Option 16: Consider water solubility in relation to test waiving


In the already submitted lead dossier of ZnO the substance is concluded to be “slightly soluble (0.1 –

100 mg/L)”. It can therefore be inferred that nano ZnO would at least exhibit the same water

solubility properties. Due to the assumed similar water solubility properties it can reasonably be

argued that in both cases - update of the lead dossier and creation of a new lead dossier – the

registrant would mostly perform the same testing strategy (e.g. for the (eco)toxicological

compartment) as it has been conducted in the course of the preparation of the lead dossier for ZnO.

Consequently nano ZnO can be regarded as water soluble and therefore avoiding of tests – due to

water-insoluble properties – cannot be applied on nano ZnO.

The project team has no detailed information on water solubility properties of silanes which function

as surface treating materials – nevertheless, the project team assumes that the surface treating

substances (i.e. silanes) could be assumed to exhibit water insoluble properties at macro-size and

therefore waiving – due to water-insolubility – might be applicable for avoiding tests. Since it has

been noted on several occasions within the elaborated options that water-insolubility is not

applicable on nanomaterials (due to dispersion effects) additional tests would have to be performed

for the two surface treated nanoforms of ZnO if other non-testing methods, such as read-across,

grouping, (Q)SAR or exposure-based waiving are not applicable.

After screening column 2 of the Annexes VII-IX for waiving of required tests due to the low water

solubility, following tests have been identified which would be affected by the option:




- Activated sludge respiration inhibition testing (Annex VIII, 9.1.4)

- Hydrolysis as a function of pH (Annex VIII, 9.1.4)

- Simulation testing on ultimate degradation in surface waters (Annex IX, 9.2.1.2)

If no other non-testing methods are available, such as read-across, (Q)SAR or waiving due to

exposure, following testing costs would incur for each surface treated substance:



VII, 9.1.1) (OECD 202) 3,600 – 4,900


9.1.2) (OECD 201) 3,000 – 5,841



209) 3,000 – 3,087

Hydrolysis as a function of pH (Annex VIII, 9.2.2.1) (OECD 111) 6,200 – 7,032

Simulation testing on ultimate degradation in surface waters (Annex IX, 35,000 – 56,000

IHCP/2011/I/05/27/OC – Annex 2 23

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9.2.1.2) (OECD 309)


summaries 6,000

∑: 60,700 – 89,063

After a brief screening of the submitted information on the abovementioned tests, it has been

recognised that an assessment has already been conducted with nano ZnO (e.g. toxicity to aquatic

algae, short-term toxicity on fish and toxicity on microorganisms).

Referring to the postulated properties of the surface treating materials, as described above, the

outlined 6 tests would be performed with two surface treated nanoforms of ZnO which would lead to

additional efforts between 121,400 € and 178,126 €.


Size as identifier:


such as silanised nano ZnO, could be included. As already explained in detail, ZnO has been

characterised as “slightly soluble (0.1 – 100 mg/L)” in the lead dossier. It can reasonably be assumed

that nano ZnO would exhibit at least the same properties on water solubility. Therefore the outlined

tests could not be waived due to water-insoluble properties and performing of tests could be

regarded as mandatory in order to fulfill the information requirements of the correlating endpoints.

But, as also explained above, the two surface treated nanoforms of ZnO might be considered as

water-insoluble due to the physico-chemical properties of the surface treating materials. In this case

tests, as outlined in the table above, would be performed with two surface treated nanomaterials of

ZnO. Depending on the tonnage bands which would be covered in the lead dossier, a different cost

structure would incur. The project team has allocated the incurred costs in relation to the tonnage

band:

Resulting additional costs if lead dossier covers only a tonnage band between 1-10 t/y (Annex VII):

IHCP/2011/I/05/27/OC – Annex 2 24

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Required tests according to

Annexes VII-IX in REACH

Testing costs

(€)

triethoxycaprylylsilane-

coated nano ZnO

dimethoxy-

diphenylsilane/triethoxy-

caprylylsilane

crosspolymer-coated

nano ZnO

Short-term toxicity on

invertebrates 3,600 – 4,900 + +

growth inhibition study

aquatic plants (algae

preferred)

3,000 – 5,841 + +

Monitoring of each test,

completion of IUCLID

endpoints and endpoint

summaries

1,000 per test

(2,000 € for

two tests)

+ +

∑: 8,600 – 12,741 8,600 – 12,741

Additional costs for substances manufactured or imported in quantities of one tonne or

more per year (Annex VII): 17,200 € – 25,482 €

Resulting additional costs if lead dossier covers a tonnage band between 10-100 t/y (Annex VIII):

Required tests according to

Annexes VII-IX in REACH

Testing costs

(€)

triethoxycaprylylsilane-

coated nano ZnO

dimethoxy-

diphenylsilane/triethoxy-

caprylylsilane

crosspolymer-coated

nano ZnO

Short-term toxicity on

invertebrates 3,600 – 4,900 + +

growth inhibition study

aquatic plants (algae

preferred)

3,000 – 5,841 + +

short-term toxicity on fish 3,900 – 6,203 + +


inhibition testing 3,000 – 3,087 + +


Monitoring of each test,

completion of IUCLID

endpoints and endpoint

summaries

1,000 per test + +

∑: 24,700 – 32,063 24,700 – 32,063

IHCP/2011/I/05/27/OC – Annex 2 25

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more per year Annex VII + VIII): 49,400 € - 64,126 €

Resulting additional costs if lead dossier covers a tonnage band between 100-1,000 t/y (Annex IX):

The cost structure for this case has already been elaborated above (size as characteriser):


more per year Annex VII - IX): 121,400 € – 178,126 €


toxicity

Implementing option 17 in the REACH Regulation would affect information requirements of

Paragraphs 9.1.5 and 9.1.6 of Annex IX. The current approach of fulfilling the information

requirements of Annex IX foresees performing long-term tests if no adequate testing results can be

gained via short-term tests due to low water solubility (as stated in column 2 of Annex VII, 9.1.1 and

VIII, 9.13). The aspect of solubility/dispersion of nanomaterials has already been mentioned in the

evaluation of other options with the result that the argument of water-insolubility cannot be applied

on nanomaterials. Following the argumentation of the proposed recommendation in Option 17,

long-term testing proposals would be considered as obligatory until the performed chemical safety

assessment according to Annex I indicates no further need for an in-depth ecotoxicological

characterisation.

Substance as characteriser:

The project team has already indicated that it is not in the scope of the report to carry out an in-

depth literature research, to perform a data-gap analysis or to propose a testing strategy for nano

ZnO. Therefore a possible result of a chemical safety assessment cannot be predicted and it can

therefore not be inferred whether long-term tests on aquatic organisms would be required or not. In

this context the project team claims that long-term tests on aquatic organisms might be proposed by

the registrant. If in the course of the dossier evaluation ECHA concludes that the proposed testing

may be the only possibility to provide information on the aquatoxic properties, the lead registrant

would have to perform the following tests and would supplement the current lead dossier with the

testing outcomes for nano ZnO:



(Annex IX, 9.1.5)

11,000 – 18,092



30,000 – 30,823

IHCP/2011/I/05/27/OC – Annex 2 26

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or




IX, 9.1.6.2)

or


11,000– 27,413

16,000 – 21,466


∑: 24,000 – 50,915

Based on various water solubility tests ZnO has been characterized as “slightly soluble (0.1 – 100

mg/L)” in the lead dossier. Based on these findings it can reasonably be assumed that nano ZnO

would exhibit at least the same water solubility properties. A brief screening of submitted

information on aquatic toxicity reveals that nano ZnO has indeed been assessed via short-term

toxicity to aquatic invertebrates and short-term toxicity on fish. However, two surface treated

nanoforms of ZnO have not been assessed via tests on aquatic toxicity.

If aquatoxicity of surface treated nano ZnO would have to be assessed, additional testing costs would

occur if information on aquatic hazard cannot be retrieved by other means, such as read-across,

(Q)SAR or grouping. Performing of the testing regime would lead to additional costs between 48,000

€ and 101,830 € for two surface treated nano forms of ZnO.


Size as identifier:

In case of elaborating a separate lead dossier for nano ZnO also information on further nanoforms,

such as silanised nano ZnO, could be included. In the course of preparing a new dossier long-term

aquatoxic tests would be performed with two surface treated nanoforms of ZnO if short-term testing

should have been waived. Performing of long-term tests would result in additional costs between

48,000 € – 101,830 € (for derived cost structure see table above for the case of size being considered

as a characteriser.

Additional costs: 48,000 € – 101,830 € (only if lead dossier covers a tonnage band of more

than 100 t/y)

IHCP/2011/I/05/27/OC – Annex 2 27

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This option would affect the information requirements which are defined in Paragraph 9.1.2 of

Annex VII. According to the current wording of Column 2, a study on algae does not need to be

conducted if the substance is highly insoluble in water. It is considered that this argument cannot be

applied on nanomaterials, since homogenous dispersions can also be generated with water insoluble

particles which subsequently can be taken up in the organism.

Based on results of a water solubility test which has been performed by the lead registrant with the

bulk form, ZnO has been characterised as slightly soluble (0.1 – 100 mg/L). Therefore it can

reasonably be inferred that nano ZnO would at least exhibit the same water solubility and that

against this background no arguments can be applied in order to avoid (waive) the required testing.

Based on the physico-chemical properties of the surface treating substances it could reasonably be

assumed that silanised bulk forms of ZnO might exhibit water-insoluble properties. Since performing

of algal inhibition tests with two surfaced treated nanoforms of ZnO has already been identified as a

required test after a possible implementation of the proposed requirements of Option 16 in the

REACH Regulation, it can reasonably be argued that a second performing of the same test can be

omitted.




Column 2 of REACH Annexes IX, 9.4 and X, 9.4 points explicitly out the fact that the required tests do

not need to be performed if direct or indirect exposure to the affected compartment is unlikely.

Furthermore, long-term toxicity testing should be taken into account instead of short-term if the

tested substance has a high potential to adsorb to soil or is very persistent (Annex IX, 9.4). Long-term

tests should per se be proposed if the outcome of the chemical safety assessment indicates the need

for a subsequent assessment of hazardous effects.

In the course of assessing sediment toxicity and toxicity to soil microorganisms only ZnO has been

subjected to an in-depth toxicological characterisation.

Since the lead dossier for ZnO covers only a tonnage band between 100 and 1000 t/y only

information requirements of Annex IX would have to be fulfilled. In the case of Option 19 testing of

effects on soil micro-organisms (Annex IX – 9.4.2; OECD 216/217; 5,850 € – 18,263 €) with nano ZnO

and two surface treated nanoforms of ZnO would have to be performed if exposure to soil would be

regarded as probable. Performing and monitoring of test, completion of IUCLID endpoint and

endpoint summaries would lead to additional costs between 20,550 € and 57,789 € for three tested

nanoforms of ZnO.


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Size as identifier:

In case of elaborating a separate lead dossier for nano ZnO also information on further nanoforms,


Since the project team has no information on emissions of three nanoforms of ZnO, it assumes – due

to reasons of simplicity – that emission to soil compartment might be of relevance.

The cost structure, as outlined above, would occur only if the lead dossier would cover a tonnage

band of more than 100 tonnes or more per year. If the tonnage band of the lead dossier is below this

threshold, no further costs would occur for the registrant. Unfortunately the project team has no

indications from the Zn REACH Consortium with regard any intentions to elaborate and submit a lead

dossier for nano ZnO.

Additional costs: 20,550 € – 57,789 € (if lead dossier covers a tonnage band of more than

100 tonnes per year)




With regard to the exposure assessment and risk characterisation, a re-evaluation of exposure

estimates and PNEC/DNEL would be required in order to take in account further metrics which are

considered to be more (or equally) relevant than the mass metric.

The project team assumes that additional efforts of 2 working days for each nanoform of ZnO would

be required in order to take additional metrics into account and to update the CSR and the relevant

IUCLID endpoints. These steps would lead to total costs of 6,000 € for the three nanoforms of ZnO.


Size as identifier:

In the case of the elaboration of a separate lead dossier for nano ZnO the same cost structure would

occur, as explained above, if the lead dossier would cover a tonnage band of more than 10 tonnes

year. According to Article 14 of the REACH Regulation – a chemical safety assessment should be

performed and a chemical safety report should be completed only for those substances which are

manufactured or imported in quantities of more than 10 tonnes per year.

Additional costs: 6.000 € (if nano ZnO is manufactured/imported in quantities of more

than 10 tonnes per year)

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5 Case study for nano diamond

As already explained in the main report a lead registrant dossier for crystalline synthetic diamond in

the tonnage band of 100 – 1,000 t/y has been submitted at ECHA. The lead dossier explicitly excluded

the presence of nano diamond. In the context of further cost assessment the project team assumes

that only one non-surface treated nanoform of diamond will be relevant.

Option 6: Include information on dustiness



already submitted lead dossier. Referring on the outcomes of the RIP-oN2 report, measurements on






current testing methods in order to characterize nanomaterials more appropriate. Taking into


approximately 500 €, the performing of test on dustiness would result in total testing costs of

1,100 €. The elaboration of the corresponding IUCLID endpoint and the endpoint summary would

result in additional costs of 1,000 € (equivalent to one working day).


Size as identifier:


preparing a lead dossier for nano diamond.


Option 11: Require acute toxicity data for the most relevant route of exposure (Annex VII)


As the lead dossier for diamond does not refer to nano diamond, the data for acute toxicity has to be

included in the lead dossier update for those endpoints for which the data of nano diamond differ

from data of diamond. As explained in the beginning, when the lead dossier for diamond will be

updated, data according to REACH Annexes VII, VIII and IX have to be submitted. This means that

besides a test on acute toxicity oral with nano diamond, also a second study on acute toxicity

inhalation with nano diamond has to be performed. Furthermore, according to the provisions laid

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out in the Annexes, an acute oral toxicity study does not need to be performed if data of an acute

inhalation toxicity study are available.

Consequently the registrant would have to consider performing of an acute inhalation toxicity test

(e.g. according to OECD GD 39 (Guidance document on acute inhalation toxicity testing)) for nano

diamond. Performing of the test (8,300 € – 19,000 €), test monitoring and completion of the IUCLID

endpoint and the summary are regarded to lead to additional costs between 9,300 € and 20,000 €

for one tested nanoform (if no other non-testing approaches, such as read-across or (Q)SAR are

applicable). Additional costs would occur if subsequent pathology/histology would have to be

performed and a focus would have to be laid on the examination of the BAL fluid. Given that

pathology/histology and the examination of the BAL fluid would require efforts of two working days

(equivalent to 2,000 €), the project team assumes furthermore that the accompanying analytical

detection would incur additional costs of 1,500 €. In summary, a possible implementation of

information requirements of Option 11 in the REACH Regulation would lead to additional costs

between 12,800 € and 23,500 €.


Size as identifier:

In case a separate lead dossier has to be elaborated for nano diamond, the relevant tonnage band

would be 1-10 t/y resulting in information requirements according to Annex VII only. In case Annex

VII is modified in a way that for nanomaterials an acute toxicity study on inhalation (according to

OECD GD 39 (Guidance document on acute inhalation toxicity testing)) is required for nanomaterials,

additional costs between 12,800 € and 23,500 € (incl. test monitoring, completion of IUCLID endpoint

and summary) will arise.


Option 12: Change „particles“ to „(nano)particles“ for repeated dose toxicity studies

(inhalation)


As the lead dossier for diamond does not refer to nano diamond, the data for repeated dose toxicity

has to be included in the update of the existing lead dossier in any case. As explained in the

beginning, when the lead dossier for diamond will be updated, data according to REACH Annexes VII,

VIII and IX have to be submitted. This means that changes in Annex VIII are relevant. However,

inhalation has been considered to be the most relevant route of exposure for diamond in the existing

lead dossier whereas the long-term testing has been waived.





IHCP/2011/I/05/27/OC – Annex 2 31

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Size as identifier:


would be 1-10 t/y resulting in information requirements according to Annex VII only. In case Annex

VIII and IX are modified in the proposed way, this will not have an impact on costs for dossier

elaboration.


Option 13: Require non-bacterial in vitro gene mutation study


As the lead dossier for diamond does not refer to nano diamond, data for mutagenicity has to be

considered for the update of the existing lead dossier in any case. When the lead dossier for diamond

will be updated, data according to REACH Annexes VII, VIII and IX have to be submitted and in case a

non-bacterial in vitro gene mutation study has to be performed as suggested by this option

additional costs can be expected.

Studies with mammalian cells or the proposed additional tests are assumed to be more expensive

that an Ames test. Performing of the test (e.g. in vitro micronucleus test in mammalian cells

according to OECD 487; 19,000 € – 23,000 €), test monitoring and completion of the IUCLID endpoint

and the summary would result in additional costs between 20,000 € and 24,000 € for testing nano

diamond, if considered necessary. As already explained in the case study for nano ZnO, the Ames test

is considered as not fully adequate for assessment of nanomaterials. Therefore, the Ames test is not

further considered in the cost calculation – instead, as outlined above, more appropriate test

methods are taken into account.


Size as identifier:


would be 1-10 t/y resulting in information requirements according to Annex VII only.

Performing of the test (e.g. in vitro micronucleus test in mammalian cells according to OECD 487;

19,000 € – 23,000 €), test monitoring and completion of the IUCLID endpoint and the summary

would result in additional costs between 20,000 € - 24,000 € for one tested nanoform.


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Option 16: Consider water solubility in relation to test waiving


An updated lead dossier would have to be amended and updated with tests which are obligatory

according to the Annexes VII to IX. All tests would have to be carried out for which the argument of

water insolubility (as stated in column 2) is not applicable.

After screening column 2 of Annexes VII-IX for tests which can be waived due to low water solubility

of the testing substance, following tests have been identified which would be affected by this option:




- Activated sludge respiration inhibition testing (Annex VIII, 9.1.4)

- Hydrolysis as a function of pH (Annex VIII, 9.1.4)

- Simulation testing on ultimate degradation in surface waters (Annex IX, 9.2.1.2)



VII, 9.1.1) (OECD 202) 3,600 – 4,900


9.1.2) (OECD 201) 3,000 – 5,841



209) 3,000 – 3,087

Hydrolysis as a function of pH (Annex VIII, 9.2.2.1) (OECD 111) 6,200 – 7,032

Simulation testing on ultimate degradation in surface waters (Annex IX,

9.2.1.2) (OECD 309) 35,000 – 56,000


summaries 6,000

∑: 60,700 – 89,063

Performing of the tests, test monitoring and completion of the IUCLID endpoint would lead finally to

additional costs between 60,700 € and 89,063 € for the outlined testing regime.

Additional costs: 60,700 – 89,063 €

Size as identifier:

It has initially been assumed that just a limited number of potential registrants would have the

obligation to register nano diamond. It was furthermore assumed that the tonnage band of each

registrant would be in the range between 1-10 t/y. Against this background the lead dossier would

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have to include all those information needs which have been defined in Annex VII of the REACH

Regulation.



VII, 9.1.1) (OECD 202) 3,600 – 4,900


9.1.2) (OECD 201) 3,000 – 5,841


summaries 1,000 per test

∑: 8,600 – 12,741

Referring to the cost structure – as outline in the table above – additional costs between 8,600 € and

12,741 € (testing and test monitoring of short-term toxicity on invertebrates and growth inhibition

study on algae, completion of IUCLID endpoints and summary) would occur.



toxicity


Taking into account the fact that the lead dossier for diamond would have to be updated by

assessing the ecotoxicological properties of nano diamond, following tests would have to be

performed in order to fulfill the information requirements for the specific endpoints:



(Annex IX, 9.1.5) 11,000 – 18,092



or




IX, 9.1.6.2)

or


30,000 – 30,823

11,000– 27,413

16,000 – 21,466


∑: 24,000 – 50,915

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Performing of tests which would be required after a possible implementation of the wording of

Option 17 in the REACH Regulation would lead to additional costs of 24,000 € – 50,915 €.


Size as identifier:

In the preamble to this case study it has been assumed that a lead dossier for nano diamond for a

tonnage band between 1-10 t/y would have to be prepared. Therefore only information

requirements of Annex VII would be applied on this dossier. Since a possible implementation of the

requirements of Option 17 in the REACH Regulation would affect only substances which are

registered in a tonnage band of more than 100 t/y no additional costs would incur in the course of

the elaboration of a lead dossier for nano diamond.




The abovementioned arguments have been taken into account for waiving the IUCLID endpoint 6.1.5

"Toxicity to aquatic algae and cyanobacteria". The waiving statement has been underpinned by the

testing results of the water solubility test, which has proven the insoluble character of diamond. On

the contrast to this, literature data indicate water soluble/dispersable properties of nano diamond.

Against this background the current lead dossier of synthetic diamond would be amended by adding

the testing results of the Algal Inhibition Test (e.g. according to OECD 201) with nano diamond. The

resulting costs for monitoring the test and completing the IUCLID endpoint (1 working day; 1,000 €)

and performing the test (3,000 € – 5,841 €) would lead to additional costs between 4,000 € and

6,841 €. Since this test has already been identified as a probably required test after a possible

implementation of information requirements of Option 16 in the REACH Regulation, it is no need to

repeat this test again.


Size as identifier:

In the case of elaborating a lead dossier for nano diamond it is proposed that no additional costs

would occur since performing of this test has already been identified as a required test after a

possible implementation of the requirements of Option 16 in REACH.


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In the course of the preparation of the lead dossier for synthetic diamond, the IUCLID endpoint 6.3.4

has been waived by applying the argumentation as it has been stated in column 2. Since exposure to

the soil compartment has been excluded in the case of synthetic diamond the project team assumes

that exposure of nano diamond to the same compartment would be equally likely. Consequently no

additional costs for performing tests (e.g. testing of effects on soil micro-organisms (Annex IX – 9.4.2;

OECD 216/217; 5,850 € – 18,263 €) would be required.


Size as identifier:

In the preamble to this case study it has been assumed that a lead dossier for nano diamond for a

tonnage band between 1-10 t/y would have to be prepared. Therefore only information

requirements of Annex VII would be applied on this dossier. Since the abovementioned testing needs

would be relevant for tonnage bands above 10 t/y, these tests can be regarded as not obligatory for

this case.





It is proposed that efforts of 2 working days (equivalent to 2,000 €) would be required for

considering the additional information on particle number or surface area in the elaboration of

PNEC/DNEL values or supplementing the CSR.


Size as identifier:

As stated in option 20, a chemical safety assessment would not be required for registration of nano

diamond and therefore only additional costs related to presentation of results of toxicological studies

requested in Annex VII in several metrics would arise (see option 10). Consideration of testing results

for the elaboration of PNEC/DNEL values and the CSR are considered to lead to additional costs of

2,000 €.


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Table A2-1: Overview on resulting additional costs for nano TiO2, nano ZnO, nano diamond.

*: Due to reasons of simplification the project team assumed that only nano TiO2 and surface treated nano TiO2 would be subjected to an update process or

elaboration of a new registration dossier. Resulting costs might increase with further nanoforms of TiO2.

**: Due to reasons of simplification the project team assumed that only nano ZnO and two surface treated nanoforms of ZnO would be subjected to an

update process or elaboration of a new registration dossier. Resulting costs might increase with further nanoforms of ZnO.

***: Due to reasons of simplification the project team assumed that only nano diamond would be subjected to an update process or elaboration of a new

registration dossier. Resulting costs might increase with further nanoforms of diamond.

Resulting additional costs (€) of option scenario

No. No. JRC Nano TiO2* Nano ZnO** Nano diamond***

Size as characteriser Size as identifier Size as characteriser Size as identifier Size as characteriser Size as identifier

6 3.6 2,700 2,700 4,300 4,300 2,100 2,100

11 4.5 12,800 – 23,500 12,800 – 23,500 25,600 – 47,000 25,600 – 47,000 12,800 – 23,500 12,800 – 23,500

12 4.6 0 0 0 0 0 0

13 4.7 0 0 60,000 – 72,000 60,000 – 72,000 20,000 – 24,000 20,000 – 24,000

16 4.10 103,900 – 154,095 8,600 – 154,095 121,400 – 178,126 17,200 – 178,126 60,700 – 89,063 8,600 – 12,741

17 4.11 48,000 – 101,830 48,000 – 101,830 48,000 – 101,830 48,000 – 101,830 24,000 – 50,915 0

18 4.12 0 0 0 0 0 0

19 4.13 27,250 – 56,815 6,850 – 56,815 20,550 – 57,789 20,550 – 57,789 0 0

21 5.2 4,000 4,000 6,000 6,000 2,000 2,000

∑: 198,650 – 342,940 82,950 – 342,940 285,850 – 467,045 181,650 – 467,045 121,600 – 191,078 45,500 – 64,341

Average per nanoform 99,325 – 171,470 41,475 – 171,470 95,283 – 155,682 60,550 – 155,682 120,100 – 191,078 45,500 – 64,341

Documents

ANNEX 2 TO FINAL REPORT - European Commission€¦ · Annex 2 to Final Report - Case Studies of Option Scenario Examination and assessment of consequences for industry, consumers,