1、 ISO 2016 Nanotechnologies Compilation and description of sample preparation and dosing methods for engineered and manufactured nanomaterials Nanotechnologies Compilation et description de la prparation des chantillons et des mthodes de dosage pour les nanomatriaux dingnierie et manufacturs TECHNICA
2、L REPORT ISO/TR 16196 Reference number ISO/TR 16196:2016(E) First edition 2016-10-01 ISO/TR 16196:2016(E)ii ISO 2016 All rights reserved COPYRIGHT PROTECTED DOCUMENT ISO 2016, Published in Switzerland All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or u
3、tilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below or ISOs member body in the country of the requester. ISO copy
4、right office Ch. de Blandonnet 8 CP 401 CH-1214 Vernier, Geneva, Switzerland Tel. +41 22 749 01 11 Fax +41 22 749 09 47 copyrightiso.org www.iso.org ISO/TR 16196:2016(E)Foreword v Introduction vi 1 Scope . 1 2 Normative references 1 3 T erms and definitions . 1 4 Abbreviated terms 3 5 Background 3 5
5、.1 Discussion of the importance of sample preparation and dosing 3 5.2 Discussion of specific issues when testing the toxicology of manufactured nanomaterials 4 5.2.1 Physical properties 4 5.2.2 Sample preparation . 4 5.2.3 Administration of doses. 5 5.2.4 Discussion of relationship between this doc
6、ument and ISO/TR 13014 5 5.3 Discussion of relevant dosing for toxicological screening . 5 5.4 Discussion of the relationship between this document and ISO/TR 16197 5 5.5 Review of other relevant international activities and documents . 5 6 Physico-chemical properties . 6 6.1 Particle size, shape, s
7、ize distribution and degree of agglomeration . 6 6.2 Chemical description Composition and identification 6 6.3 Specific surface area . 6 6.4 Surface chemistry . 6 6.5 Isoelectric point, zeta potential and Hamaker constant . 7 6.6 Influence of water chemistry on nanomaterial properties and dispersion
8、 behavior 8 6.7 Preparation of liquid dispersions . 8 6.8 Crystal structure 8 6.9 Surface energy or interfacial tension . 8 6.10 Solubility 8 7 Considerations for preparing samples of nanomaterials in exposure media in ecotoxicity studies 9 7.1 General . 9 7.1.1 Introduction to existing knowledge 9
9、7.1.2 Environmental behaviour 9 7.1.3 Degradation and transformation . 9 7.1.4 Bioaccumulation 9 7.2 Test method applicability and dosimetry .10 7.2.1 Environmental distribution .10 7.2.2 Degradation and transformation 10 7.2.3 Bioaccumulation .11 8 Methods for preparing nanomaterials for toxicologi
10、cal studies in mammals that ensure correct dosing .11 8.1 Issues to consider for stock dispersion preparation .11 8.2 Importance of monitoring stability of test dispersions during experiments .11 8.3 Special considerations for physiological salines used in mammalian studies 12 8.4 Routes of delivery
11、 and behaviour of nanomaterial dispersions in mammalian studies 12 8.4.1 Respiratory tract exposures 12 8.4.2 Oral exposure .12 8.4.3 Dermal exposures 13 8.4.4 Injection routes 13 9 Methods for preparing samples of nanomaterials for use in cell cultures .13 9.1 Cell cultures and dispersion of nanoma
12、terials in culture media 13 9.1.1 General.13 ISO 2016 All rights reserved iii Contents Page ISO/TR 16196:2016(E)9.1.2 Considerations for nanomaterial dispersion in the dosing solution .13 9.1.3 Consideration of relevant exposure scenarios 14 9.2 Cell cultures 14 Bibliography .16 iv ISO 2016 All righ
13、ts reserved ISO/TR 16196:2016(E) Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body inte
14、rested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnica
15、l Commission (IEC) on all matters of electrotechnical standardization. The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO docu
16、ments should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives). Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. ISO shall not be held responsi
17、ble for identifying any or all such patent rights. Details of any patent rights identified during the development of the document will be in the Introduction and/or on the ISO list of patent declarations received (see www.iso.org/patents). Any trade name used in this document is information given fo
18、r the convenience of users and does not constitute an endorsement. For an explanation on the meaning of ISO specific terms and expressions related to conformit y assessment, as well as information about ISOs adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trad
19、e (TBT) see the following URL: www.iso.org/iso/foreword.html. The committee responsible for this document is ISO/TC 229, Nanotechnologies. ISO 2016 All rights reserved v ISO/TR 16196:2016(E) Introduction This document provides guidance regarding the preparation of nanomaterials for toxicological, in
20、cluding eco-toxicological, testing. The goal of this document is to assist health and environmental scientists and scientists and experts from other disciplines to understand, plan, choose and address issues relevant to nanomaterials before and during conducting toxicological tests. These issues inc
21、lude the effects of the properties of the material on preparation methods and of the media into which the samples of nanomaterials will be added. Failure to consider these effects might lead to erroneous conclusions regarding the relationship between the nature of the nanomaterial and observed toxic
22、ological responses. In particular, the composition and other characteristics of test media can affect the dose to which an organism that is the subject of a test will be exposed. Information on preparation of the test material is necessary prior to any biological or ecological evaluation. Informatio
23、n such as this is consistent with other ISO documents. For example, ISO 10993-18 1specifically addresses the evaluation of the chemical characterization of materials used in medical devices, ISO 14971 2specifies that a toxicological risk analysis should take into account the chemical nature of the m
24、aterials, ISO/TR 13014 3addresses issues pertaining to the materials themselves and ISO/TS 19337 55points out the need to clarify whether observed toxic effects come from tested nano-objects themselves or from other uncontrolled sources. Some examples are provided of methods that establish test cond
25、itions that are relatable to environmentally relevant conditions. This document uses a number of technical terms which have been defined earlier in other documents. Some of these terms have been defined in multiple documents, in different areas of science and technology, providing potentially or see
26、mingly conflicting definitions. This document does not provide new, authoritative definitions for the terms used herein. Instead, this clause provides short descriptions for the terms used. Where possible, reference is made to existing documents.vi ISO 2016 All rights reserved Nanotechnologies Compi
27、lation and description of sample preparation and dosing methods for engineered and manufactured nanomaterials 1 Scope This document provides guidance regarding the preparation of nanomaterials for eco- and bio- toxicological testing. It provides guidance regarding factors pertaining to sample prepar
28、ation and dose determination that might be useful in toxicological, including ecotoxicological, testing of engineered and manufactured nanoscale materials. The descriptions of sample preparation method factors for both in vitro and in vivo toxicological testing of engineered and manufactured nanosca
29、le materials include considerations about physico-chemical properties, media, methods for transformation and accumulation studies, health effects and dosimetry. The document is not intended to be a literature review nor a thorough assessment of the quality of the methods or data generated. The docum
30、ent is intended to complement other international efforts. The focus of this document is on factors that might lead to results that are not relevant to safety evaluations. When featured, referenced methods are considered for their general interest and potential applicability. It is likely that most
31、of the described methods are not generally applicable to all nanomaterials but they do demonstrate important factors and limitations that are common for a variety of nanomaterials. 2 Normative references There are no normative references in this document. 3 T erms a nd definiti ons For the purposes
32、of this document, the following terms and definitions apply. ISO and IEC maintain terminological databases for use in standardization at the following addresses: IEC Electropedia: available at http:/ /www.electropedia.org/ ISO Online browsing platform: available at http:/ /www.iso.org/obp 3.1 partic
33、le minute piece of matter with defined physical boundaries Note 1 to entry: A physical boundary can also be described as an interface. Note 2 to entry: A particle can move as a unit. Note 3 to entry: This general particle definition applies to nano-objects. SOURCE: ISO/TS 80004-2:2015, 3.1 3.2 struc
34、ture arrangement defined by four different aspects (crystallinity, crystal structure, molecular structure and microstructure) TECHNICAL REPORT ISO/TR 16196:2016(E) ISO 2016 All rights reserved 1 ISO/TR 16196:2016(E) 3.2.1 crystallinity presence or absence of crystalline structure in the arrangement
35、of the atoms of which a material consists 3.2.2 crystal structure lattice structure in which atoms of an individual crystal are arranged, using lattice parameters and lattice type, such as face-centred cubic, hexagonal close-packed, body-centred, cubic, etc. 3.2.3 molecular structure arrangement of
36、atoms of an individual molecule 3.2.4 microstructure arrangement of individual crystals or amorphous phases in a polycrystalline or multiphase material 3.3 measurand quantity intended to be measured or a quantity that is being determined by measurement Note 1 to entry: The specification of a measura
37、nd requires knowledge of the kind of quantity, description of the state of the phenomenon, body, or substance carrying the quantity, including any relevant component, and the chemical entities involved. The measurement, including the measuring system and the conditions under which the measurement is
38、 carried out, might change the phenomenon, body, or substance so that the quantity being measured may differ from the measurand as defined. SOURCE: ISO/IEC Guide 99, 2007, 2.3 modified 3.4 nanomaterial NM material with any external dimension in the nanoscale or having internal structure or surface s
39、tructure in the nanoscale Note 1 to entry: This generic term is inclusive of nano-object and nanostructured material. Note 2 to entry: See also engineered nanomaterial, manufactured nanomaterial, incidental nanomaterial. SOURCE: ISO/TS 80004-1:2015, 2.4 3.5 nano-object discrete piece of material wit
40、h one, two or three external dimensions in the nanoscale Note 1 to entry: The second and third external dimensions are orthogonal to the first dimension and to each other. SOURCE: ISO/TS 80004-2:2015, 2.2 3.6 nanoparticle NP nano-object with all external dimensions in the nanoscale where the lengths
41、 of the longest and the shortest axes of the nano-object do not differ significantly Note 1 to entry: If the dimensions differ significantly (typically by more than three times), terms, such as n an o f ib r e or nanoplate, may be preferred to the term nanoparticle. SOURCE: ISO/TS 80004-2:2015, 4.42
42、 ISO 2016 All rights reserved ISO/TR 16196:2016(E) 3.7 nanoscale length range approximately from 1 nm to 100 nm Note 1 to entry: Properties that are not extrapolations from a larger size are predominantly exhibited in this length range. SOURCE: ISO/TS 80004-2:2015, 2.1 4 Abbreviated terms BET Brunau
43、erEmmettTeller isotherm CNT carbon nanotube DLS dynamic light scattering ICP-MS inductively coupled plasma mass spectrometry NOAA nano-objects, and their aggregates and agglomerates greater than 100 nm NOM natural organic material TEM transmission electron microscopy 5 Background 5.1 Discussion of t
44、he importance of sample preparation and dosing Nanomaterials are diverse, being based on endless combinations of composition, particle size and distribution, surface chemistry and many other key properties. With this diversity, nanomaterials cannot be treated as a single class of substances. Just as
45、 in other areas of toxicology, the assessment of biological effects should consider how samples and doses are prepared and dosimetry is assured so that the observed effects are meaningful and test results can be used in a realistic way such as in safety assessments. Screening tests are used for rapi
46、d evaluations and are typically conducted using cell culture or other in vitro techniques due to fast response time, cost, infrastructure and time constraints, factors that limit most whole animal studies. The purpose of a screening test is to provide an indicator of potential adverse outcomes and e
47、ffects on human health or the environment. Although there are many definitions available for the term screening test, for the purposes of this document, a screening test can be generally defined as a relatively simple, inexpensive test that can be administered easily and provides rapid results. The
48、screening tests should reflect the compromise between simplicity, rapidity and low- cost while still providing results that have meaning to safety-relevant situations, the way that samples are prepared and the doses administered will ideally be relatable to realistic situations. Therefore, the point
49、s considered in this document also apply to screening tests and should also be taken into account in tiered testing to ensure consistent conditions with each step of the tier. ISO 2016 All rights reserved 3 ISO/TR 16196:2016(E) 5.2 Discussion of spec ific issues w hen t esting the t o xic ology of manufactur ed nanomaterials 5.2.1 Physical properties 5.2.1.1 General The subject that is sometimes referred to as “nanotoxicology” considers the same issues as the broader subject of toxicology with additional scrutiny
