Ansi Aami Iso 10993-3-2003 R2013

American
National
Standard
ANSI/AAMI/
ISO 10993-3:
2003/(R)2013
Bi ol og i cal eval u ati on of
m ed i cal d evi ces — Part 3 :
Tests for g en otoxi ci ty,
carci n og en i ci ty, an d
reprod u cti ve toxi ci ty
Copyright Association for the Advancement of Medical Instrumentation

The Objectives and Uses of AAMI Standards and
Recommended Practices
It is most important that the obj ectives and potential uses of an AAMI Each AAMI standard or recommended practice reflects the
product standard or recommended practice are clearly understood. collective expertise of a committee of health care professionals and
The obj ectives of AAMI's technical development program derive industrial representatives, whose work has been reviewed nationally
from AAMI's overall mission: the advancement of medical (and sometimes internationally). As such, the consensus
instrumentation. Essential to such advancement are (1 ) a continued recommendations embodied in a standard or recommended practice
increase in the safe and effective application of current technologies are intended to respond to clinical needs and, ultimately, to help
to patient care, and (2) the encouragement of new technologies. It is ensure patient safety. A standard or recommended practice is limited,
AAMI's view that standards and recommended practices can however, in the sense that it responds generally to perceived risks and
contribute significantly to the advancement of medical conditions that may not always be relevant to specific situations. A
instrumentation, provided that they are drafted with attention to these standard or recommended practice is an important re fe re n ce in
obj ectives and provided that arbitrary and restrictive uses are avoided. responsible decision-making, but it should never re p la c e responsible
A voluntary s ta n da rd for a m e dica l de vice recommends to the decisionmaking.
manufacturer the information that should be provided with or on the Despite periodic review and revision (at least once every five
product, basic safety and performance criteria that should be con- years), a standard or recommended practice is necessarily a static
sidered in qualifying the device for clinical use, and the measurement document applied to a dynamic technology. Therefore, a standards
techniques that can be used to determine whether the device conforms user must carefully review the reasons why the document was
with the safety and performance criteria and/or to compare the per- initially developed and the specific rationale for each of its
formance characteristics of different products. S ome standards em- provisions. This review will reveal whether the document remains
phasize the information that should be provided with the device, relevant to the specific needs of the user.
including performance characteristics, instructions for use, warnings Particular care should be taken in applying a product standard to
and precautions, and other data considered important in ensuring the existing devices and equipment, and in applying a recommended
safe and effective use of the device in the clinical environment. practice to current procedures and practices. While observed or
Recommending the disclosure of performance characteristics often potential risks with existing equipment typically form the basis for the
necessitates the development of specialized test methods to facilitate safety and performance criteria defined in a standard, professional
uniformity in reporting; reaching consensus on these tests can j udgment must be used in applying these criteria to existing equip-
represent a considerable part of committee work. When a drafting ment. No single source of information will serve to identify a
committee determines that clinical concerns warrant the establishment particular product as " unsafe" . A voluntary standard can be used as
of m in im u m safety and performance criteria, referee tests must be one resource, but the ultimate decision as to product safety and
provided and the reasons for establishing the criteria must be efficacy must take into account the specifics of its utilization and, of
documented in the rationale. course, cost-benefit considerations. Similarly, a recommended
A re co m m e n de d p ra ctic e provides guidelines for the use, care, practice should be analyzed in the context of the specific needs and
and/or processing of a medical device or system. A recommended resources of the individual institution or firm. Again, the rationale
practice does not address device performance p er se , but rather accompanying each AAMI standard and recommended practice is an
procedures and practices that will help ensure that a device is used excellent guide to the reasoning and data underlying its provision.
safely and effectively and that its performance will be maintained. In summary, a standard or recommended practice is truly useful
Although a device standard is primarily directed to the manufac- only when it is used in conj unction with other sources of information
turer, it may also be of value to the potential purchaser or user of the and policy guidance and in the context of professional experience and
device as a fume of reference for device evaluation. S imilarly, even j udgment.

though a recommended practice is usually oriented towards health
care professionals, it may be useful to the manufacturer in better INTERPRETATIONS OF AAMI STANDARDS
understanding the environment in which a medical device will be AND RECOMMENDED PRACTICES
used. Also, some recommended practices, while not addressing device
performance criteria, provide guidelines to industrial personnel on Requests for interpretations of AAMI standards and recommended
such subj ects as sterilization processing, methods of collecting data to practices must be made in writing, to the Manager for Technical
establish safety and efficacy, human engineering, and other Development. An official interpretation must be approved by letter
processing or evaluation techniques; such guidelines may be useful to ballot of the originating committee and subsequently reviewed and
health care professionals in understanding industrial practices. approved by the AAMI Standards B oard. The interpretation will
In determining whether an AAMI standard or recommended become official and representation of the Association only upon
practice is relevant to the specific needs of a potential user of the exhaustion of any appeals and upon publication of notice of interpre-
document, several important concepts must be recognized: tation in the "S tandards Monitor" section of the A A MI Ne w s . The
All AAMI standards and recommended practices are vo lu n ta ry Association for the Advancement of Medical Instrumentation
(unless, of course, they are adopted by government regulatory or disclaims responsibility for any characterization or explanation of a
procurement authorities). The application of a standard or recom- standard or recommended practice which has not been developed and
mended practice is solely within the discretion and professional communicated in accordance with this procedure and which is not
j udgment of the user of the document. published, by appropriate notice, as an o fficia l in te rp re ta tio n in the
A A MI Ne w s .

Ameri can N ati on al Stan d ard AN SI /AAM I /I SO 1 0993-3: 2003/(R)201 3
(Revi si on of AN SI /AAM I /I SO 1 0993-3: 1 993)
B i ol og i cal eval u ati on of m ed i cal d evi ce s —P art 3 :
Tes ts for g en otoxi ci ty, carci n og en i ci ty, an d
reprod u cti ve toxi ci ty
Approved 8 October 2003 by

As soci ati on for th e Ad van cem en t of M ed i cal I n stru m en tati on
Approved 23 October 2003 an d reaffirmed 26 N ovember 201 3 by

Am eri can N ati on al Stan d ard s I n sti tu te, I n c.
Abs tract: Speci fi es strateg i es for h azard i d en ti fi cati on an d tests on m ed i cal d evi ces for g en otoxi ci ty,
carci n og en i ci ty, an d reprod u cti ve an d d evel opm en tal toxi ci ty.
Keyword s : biolog ical evalu ati on, genotoxicity, carci nog en icity, med ical d evices, reprod u ctive an d devel opmental
toxi ci ty

AAMI Standard
This Association for the Advancement of Medical Instrumentation (AAMI) standard implies a consensus of those
substantially concerned with its scope and provisions. The existence of an AAMI standard does not in any respect
preclude anyone, whether they have approved the standard or not, from manufacturing, marketing, purchasing, or
using products, processes, or procedures not conforming to the standard. AAMI standards are subject to periodic
review, and users are cautioned to obtain the latest editions.
CAUTION NOTICE: This AAMI standard may be revised or withdrawn at any time. AAMI procedures require that
action be taken to reaffirm, revise, or withdraw this standard no later than 5 years from the date of publication.
Interested parties may obtain current information on all AAMI standards by calling or writing AAMI.
All AAMI standards, recommended practices, technical information reports, and other types of technical documents
developed by AAMI are voluntary, and their application is solely within the discretion and professional judgment of the
user of the document. Occasionally, voluntary technical documents are adopted by government regulatory agencies
or procurement authorities, in which case the adopting agency is responsible for enforcement of its rules and
regulations.
Published by
Association for the Advancement of Medical Instrumentation
1 1 1 0 N. Glebe Road, Suite 220
Arlington, VA 22201 -4795
© 2003 by the Association for the Advancement of Medical Instrumentation
All Rights Reserved
This publication is subject to copyright claims of ISO, ANSI, and AAMI. No part of this publication may be reproduced
or distributed in any form, including an electronic retrieval system, without the prior written permission of AAMI. All
requests pertaining to this draft should be submitted to AAMI. It is illegal under federal law (1 7 U.S.C. § 1 01 , et seq.)
to make copies of all or any part of this document (whether internally or externally) without the prior written
permission of the Association for the Advancement of Medical Instrumentation. Violators risk legal action, including
civil and criminal penalties, and damages of $1 00,000 per offense. For permission regarding the use of all or any part
of this document, contact AAMI, 1 1 1 0 N. Glebe Road, Suite 220, Arlington, VA 22201 -4795. Phone: (703) 525-4890;
Fax: (703) 525-1 067.
Printed in the United States of America
ISBN 1 –57020–207–9

C on ten ts
G l ossary of eq u i val en t stan d ard s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i v
Com mi ttee represen tati on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
Backg rou n d of AN SI /AAM I ad opti on of I SO 1 0993-3: 2003 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi i
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi i i
I n trod u cti on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i x
1 Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 N orm ati ve referen ces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
3 Term s an d d efi n i ti on s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4 G en otoxi ci ty tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. 1 G en eral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. 2 Test strateg y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. 3 Sam pl e preparati on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. 4 Test m eth od s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
5 Carci n og en i ci ty tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. 1 G en eral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. 2 Test strateg y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. 4 Test m eth od s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
6 Reprod u cti ve an d d evel opm en tal toxi ci ty tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
6. 1 G en eral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
6. 2 Test strateg y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
6. 4 Test m eth od s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
7 Test report. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
An n ex A (i n form ati ve) Cel l tran sform ati on test system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
An n ex B (i n form ati ve) Rati on al e of test system s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
An n ex C (i n form ati ve) Rol e of i m pl an tati on carci n og en i ci ty stu d i es . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Bi bl i og raph y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1

G l os s ary of eq u i val en t s tan d ard s
International standards adopted in the United States may include normative references to other international
standards. For each international standard that has been adopted by AAMI (and ANSI), the table below gives the
corresponding U.S. designation and level of equivalency to the international standard. (Note: Documents are sorted
by international designation.)
Other normatively referenced international standards may be under consideration for U.S. adoption by AAMI;
therefore, this list should not be considered exhaustive.
I n tern ati on al d es i g n ati on U . S . d es i g n ati on E q u i val en cy
IEC 60601 -1 -2:2001 ANSI/AAMI/IEC 60601 -1 -2:2001 Identical

IEC 60601 -2-04:2002 ANSI/AAMI DF80:2003 Major technical variations
IEC 60601 -2-21 :1 994 and ANSI/AAMI/IEC 60601 -2-21 & Identical
Amendment 1 :1 996 Amendment 1 :2000 (consolidated texts)
IEC 60601 -2-24:1 998 ANSI/AAMI ID26:1 998 Major technical variations
ISO 5840:1 996 ANSI/AAMI/ISO 5840:1 996 Identical
ISO 71 98:1 998 ANSI/AAMI/ISO 71 98:1 998/2001 Identical
ISO 71 99:1 996 ANSI/AAMI/ISO 71 99:1 996/(R)2002 Identical
ISO 1 0993-1 :2003 ANSI/AAMI/ISO 1 0993-1 :2003 Identical
ISO 1 0993-2:1 992 ANSI/AAMI/ISO 1 0993-2:1 993/(R)2001 Identical
ISO 1 0993-3:2003 ANSI/AAMI/ISO 1 0993-3:2003 Identical
ISO 1 0993-5:1 999 ANSI/AAMI/ISO 1 0993-5:1 999 Identical
ISO 1 0993-9:1 999 ANSI/AAMI/ISO 1 0993-9:1 999 Identical
ISO 1 0993-1 0:2002 ANSI/AAMI BE78:2002 Minor technical variations
ISO 1 0993-1 1 :1 993 ANSI/AAMI 1 0993-1 1 :1 993 Minor technical variations
ISO 1 0993-1 2:2002 ANSI/AAMI/ISO 1 0993-1 2:2002 Identical
ISO 1 0993-1 3:1 998 ANSI/AAMI/ISO 1 0993-1 3:1 999 Identical
ISO 1 0993-1 6:1 997 ANSI/AAMI/ISO 1 0993-1 6:1 997/(R)2003 Identical
ISO 1 1 1 34:1 994 ANSI/AAMI/ISO 1 1 1 34:1 993 Identical
ISO 1 1 1 35:1 994 ANSI/AAMI/ISO 1 1 1 35:1 994 Identical
ISO 1 1 1 37:1 995 and Amdt 1 :2001 ANSI/AAMI/ISO 1 1 1 37:1 994 and A1 :2002 Identical
iv © 2003 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 1 0993-3:2003

I n tern ati on al d es i g n ati on U . S . d es i g n ati on E q u i val en cy
I SO 1 1 1 38-1 : 1 994 AN SI /AAM I ST59: 1 999 M aj or tech n i cal vari ati on s
I SO 1 1 1 38-2: 1 994 AN SI /AAM I ST21 : 1 999 M aj or tech n i cal vari ati on s
I SO 1 1 1 38-3: 1 995 AN SI /AAM I ST1 9: 1 999 M aj or tech n i cal vari ati on s
I SO TS 1 1 1 39: 2001 AN SI /AAM I /I SO 1 1 1 39: 2002 I d en ti cal
I SO 1 1 1 40-1 : 1 995 an d AN SI /AAM I ST60: 1 996 M aj or tech n i cal vari ati on s

Tech n i cal Corri g en d u m 1 : 1 998
I SO 1 1 607: 2003 AN SI /AAM I /I SO 1 1 607: 2000 I d en ti cal
I SO 1 1 737-1 : 1 995 AN SI /AAM I /I SO 1 1 737-1 : 1 995 I d en ti cal
I SO 1 1 737-2: 1 998 AN SI /AAM I /I SO 1 1 737-2: 1 998 I d en ti cal
I SO TR 1 3409: 1 996 AAM I /I SO TI R1 3409: 1 996 I d en ti cal
I SO 1 3485: 2003 AN SI /AAM I /I SO 1 3485: 2003 I d en ti cal
I SO 1 3488: 1 996 AN SI /AAM I /I SO 1 3488: 1 996 I d en ti cal
I SO 1 41 55-1 : 2003 AN SI /AAM I /I SO 1 41 55-1 : 2003 I d en ti cal
I SO 1 41 55-2: 2003 AN SI /AAM I /I SO 1 41 55-2: 2003 I d en ti cal
I SO 1 41 60: 1 998 AN SI /AAM I /I SO 1 41 60: 1 998 I d en ti cal
I SO 1 41 61 : 2000 AN SI /AAM I /I SO 1 41 61 : 2000 I d en ti cal
I SO 1 4969: 1 999 AN SI /AAM I /I SO 1 4969: 1 999 I d en ti cal
I SO 1 4971 : 2000 an d A1 : 2003 AN SI /AAM I /I SO 1 4971 : 2000 an d A1 : 2003 I d en ti cal
I SO 1 5223/A1 : 2002 AN SI /AAM I /I SO 1 5223: 2000/A1 : 2001 I d en ti cal
I SO TS 1 5843: 2000 AN SI /AAM I /I SO TI R1 5843: 2000 I d en ti cal
I SO TR 1 5844: 1 998 AAM I /I SO TI R1 5844: 1 998 I d en ti cal
I SO TR 1 61 42: 1 999 AN SI /AAM I /I SO TI R1 61 42: 2000 I d en ti cal
I SO 25539-1 : 2003 AN SI /AAM I /I SO 25539-1 : 2003 I d en ti cal
© 2003 Associ ati on for th e Ad van cem en t of M ed i cal I n stru m en tati on AN SI /AAM I /I SO 1 0993-3: 2003 v

C om m i tte e re pres e n tati on
As s oci ati on for th e Ad van cem en t of M ed i cal I n s tru m en tati on
B i ol og i cal E val u ati on C om m i ttee
The adoption of ISO 1 0993-3:2003 as an American National Standard was initiated by the AAMI Biological Evaluation
Committee, which also functions as a U.S. Technical Advisory Group (TAG) to the relevant work in the International
Organization for Standardization (ISO). U.S. representatives from the AAMI Genotoxicity, Carcinogenicity, and
Reproductive Toxicity Working Group (U.S. Sub-TAG for ISO/TC 1 94/WG 6), chaired by Nirmal Mishra, DVM, PhD of
the U.S. Food and Drug Administration and Robert Przygoda of Johnson & Johnson, played an active part in
developing the ISO standard.
At the time this document was published, the AAM I B i o l og i cal E val u ati on C o m m i ttee had the following members:
Cochairs: Donald E. Marlowe
Peter W. Urbanski
Members: James M. Anderson, MD, PhD, Case Western Reserve University
Eric R. Claussen, PhD, Becton Dickinson & Company
Roger Dabbah, PhD, U.S. Pharmacopeial Convention, Inc.
Lawrence H. Hecker, PhD, Abbott Laboratories
Edward Mueller, MS, Annapolis, MD
Barry F.J. Page, Garner, NC
Melvin E. Stratmeyer, PhD, U.S. Food and Drug Administration/Center for Devices and Radiological
Health/OST
Paul J. Upman, PhD, NAMSA
Peter W. Urbanski, Medtronic, Inc.
Alternates: Raju G. Kammula, DVM, PhD, U.S. Food and Drug Administration/Center for Devices and
Radiological Health/ODE
Donald E. Marlowe, U.S. Food and Drug Administration/Center for Devices and Radiological Health
Sharon J. Northup, PhD, U.S. Pharmacopeial Convention, Inc.
At the time this document was published, the AAM I G en oto xi ci ty, C arci n og en i ci ty, an d Rep rod u cti ve Toxi ci ty
Worki n g G rou phad the following members:

Cochairs: Nirmal Mishra, V, DVM, PhD
Robert Przygoda, PhD
Members: Joseph Carraway, NAMSA
Gloria H. Frost, PhD, Cardinal Health Medical Products and Services Group
Michelle A. Lee, Nelson Laboratories, Inc.
Nirmal Mishra, V, DVM, PhD, U.S. Food and Drug Administration/Center for Devices and
Radiological Health
Sharon J. Northup, PhD, U.S. Pharmacopeial Convention, Inc.
Lisa Olson, AppTec Laboratory Services
Robert T. Przygoda, PhD, Johnson & Johnson
Edward Reverdy, PhD, Boston Scientific Corporation
Anita Y. Sawyer, Becton Dickinson & Company
Brenda Seidman, PhD, Independent Expert
Kenneth R. St John, PhD, Independent Expert
Jeff M. Sturm, St Jude Medical, Inc.
Randy D. White, PhD, Baxter Healthcare Corporation
Alternates: William C. Bradbury, PhD, AppTec Laboratory Services
Lee Ellis, Boston Scientific Corporation
Chandramallika (Molly) Ghosh, PhD, NAMSA
Lawrence H. Hecker, PhD, Abbott Laboratories
Katharine Merritt, PhD, U.S. Food and Drug Administration/Center for Devices and Radiological
Health
David Porter, PhD, U.S. Pharmacopeial Convention, Inc.
Chad Summers, Nelson Laboratories, Inc.
NOTE—Participation by federal agency representatives in the development of this standard does not constitute
endorsement by the federal government or any of its agencies.
vi © 2003 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 1 0993-3:2003

Backg rou n d of AN SI /AAM I adopti on of ISO 1 0993-3: 2003
As i n d i cated in th e foreword to th e mai n bod y of th i s d ocu m en t (pag e vi i i ), th e I n tern ati on al Org an i zati on for
Stan d ard i zati on (I SO) i s a worl d wi d e fed erati on of n ati on al stan d ard s bod i es. Th e U n i ted States i s on e of th e I SO
mem bers th at took an acti ve rol e i n th e d evel opm en t of th i s stan d ard .
I n tern ati on al stan d ard I SO 1 0993-3 was d evel oped by Tech n i cal Com m i ttee I SO/TC 1 94, Bi ol og i cal eval u ati on of
med i cal d evi ces, to speci fy strateg i es for h azard i d en ti fi cati on an d tests on med i cal d evi ces for g en otoxi ci ty,
carci n og en i ci ty, an d reprod u cti ve an d d evel opm en tal toxi ci ty.
U . S. parti ci pati on in th i s I SO TC is org an i zed th rou g h th e U . S. Tech n i cal Ad vi sory Grou p for I SO/TC 1 94,
ad m i n i stered by th e Associ ati on for th e Ad van cem en t of M ed i cal I n stru m en tati on (AAM I ) on beh al f of th e Ameri can
N ati on al Stan d ard s I n sti tu te (AN SI ). Th e U . S. m ad e a con si d erabl e con tri bu ti on to th i s I n tern ati on al Stan d ard .
AAM I en cou rag es i ts com mi ttees to h arm on i ze th ei r work wi th I n tern ati on al Stan d ard s i n th e area of bi ol og i cal
eval u ati on of med i cal d evi ces as m u ch as possi bl e. U pon revi ew of I SO 1 0993-3, th e AAM I Bi ol og i cal Eval u ati on
Com mi ttee an d th e AAM I G en otoxi ci ty, Carci n og en i ci ty, an d Reprod u cti ve Toxi ci ty Worki n g G rou p proposed th e
ad opti on of 1 0993-3: 2003 verbati m as a revi si on of AN SI /AAM I /I SO 1 0993-3: 1 993.
Th i s ed i ti on of I SO 1 0993-3 i s d i fferen t from th e 1 992 ed i ti on i n th at i t ch an g es th e recom m en d ati on s for sam pl e

preparati on . Th e n ew ed i ti on provi d es opti on s for g en otoxi ci ty testi n g an d provi d es ad d i ti on al g u i d an ce for d eci d i n g
wh en to perform g en otoxi ci ty, carci n og en i ci ty, or reprod u cti ve tests. Al so, th e referen ces were u pd ated in th e
bi bl i og raph y an d several i n form ati ve an n exes were ad d ed .
AAM I an d AN SI proced u re req u i re th at Am eri can N ati on al Stan d ard s be revi ewed an d , i f n ecessary, revi sed wi th i n
fi ve years to con fi rm cu rren cy or refl ect tech n ol og i cal ad van ces th at h ave occu rred si n ce pu bl i cati on , as appropri ate.
AAM I (an d AN SI ) h ave ad opted oth er I SO stan d ard s. See th e G l ossary of Eq u i val en t Stan d ard s for a l i st of I SO
stan d ard s ad opted by AAM I , wh i ch g i ves th e correspon d i n g U . S. d esi g n ati on an d th e l evel of eq u i val en cy wi th th e
I SO stan d ard .
Th e con cepts i n corporated i n th i s stan d ard sh ou l d n ot be con si d ered i n fl exi bl e or stati c. Th i s stan d ard , l i ke an y oth er,
mu st be revi ewed an d u pd ated peri od i cal l y to assi m i l ate prog ressi ve tech n ol og i cal d evel opm en ts. To rem ai n
rel evan t, i t m u st be mod i fi ed as tech n ol og i cal ad van ces are m ad e an d as n ew d ata com es to l i g h t.
Su g g esti on s for i m provi n g th i s stan d ard are i n vi ted . Comm en ts an d su g g ested revi si on s sh ou l d be sen t to Stan d ard s
Departmen t, AAM I , 1 1 1 0 N . G l ebe Road , Su i te 220, Arl i n g ton , VA 22201 -4795.
N OTE—Beginning with the I SO foreword on pag e vi ii, th is American N ati onal Stand ard i s id entical to I SO 1 0993-3: 2003.
© 2003 Associ ati on for th e Ad van cem en t of M ed i cal I n stru m en tati on AN SI /AAM I /I SO 1 0993-3: 2003 vi i

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 interested 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 Electrotechnical
Commission (IEC) on all matters of electrotechnical standardization.
International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part 2.
The main task of technical committees is to prepare International Standards. Draft International Standards adopted
by the technical committees are circulated to the member bodies for voting. Publication as an International Standard
requires approval by at least 75 % of the member bodies casting a vote.
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 responsible for identifying any or all such patent rights.
ISO 1 0993-3 was prepared by Technical Committee ISO/TC 1 94, .
Biological evaluation of medical devices
This second edition cancels and replaces the first edition (ISO 1 0993-3:1 992), which has been technically revised.
ISO 1 0993 consists of the following parts, under the general title :
Biological evaluation of medical devices
⎯ Part 1 : Evaluation and testing
⎯ Part 2: Animal welfare requirements
⎯ Part 3: Tests for genotoxicity, carcinogenicity, and reproductive toxicity
⎯ Part 4: Selection of tests for interactions with blood
⎯ Part 5: Tests for in vitro cytotoxicity
⎯ Part 6: Tests for local effects after implantation
⎯ Part 7: Ethylene oxide sterilization residuals
⎯ Part 8: Selection and qualification of reference materials for biological tests
⎯ Part 9: Framework for the identification and quantification of potential degradation products
⎯ Part 1 0: Tests for irritation and delayed-type hypersensitivity
⎯ Part 1 1 : Tests for systemic toxicity
⎯ Part 1 2: Sample preparation and reference materials
⎯ Part 1 3: Identification and quantification of degradation products from polymeric medical devices
⎯ Part 1 4: Identification and quantification of degradation products from ceramics
⎯ Part 1 5: Identification and quantification of degradation products from metals and alloys
⎯ Part 1 6: Toxicokinetic study design for degradation products and leachables
⎯ Part 1 7: Establishment of allowable limits for leachable substances
⎯ Part 1 8: Chemical characterization of materials
Future parts will deal with other relevant aspects of biological testing.
viii © 2003 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 1 0993-3:2003
I n trod u cti on
Th e basi s for bi ol og i cal eval u ati on of med i cal d evi ces i s often em pi ri cal an d d ri ven by th e rel evan t con cern s for
h u m an safety. Th e ri sk of seri ou s an d i rreversi bl e effects, su ch as can cer or secon d -g en erati on abn orm al i ti es, i s of
parti cu l ar pu bl i c con cern . I t i s i n h eren t i n th e provi si on of safe m ed i cal d evi ces th at su ch ri sks be m i n i m i zed to th e
g reatest exten t feasi bl e. Th e assessm en t of mu tag en i c, carci n og en i c, an d reprod u cti ve h azard s i s an essen ti al
com pon en t of th e con trol of th ese ri sks. N ot al l test m eth od s for th e assessm en t of g en otoxi ci ty, carci n og en i ci ty, or
reprod u cti ve toxi ci ty are eq u al l y wel l d evel oped , n or i s th eir val i d i ty wel l establ i sh ed for th e testi n g of med i cal d evi ces.
Si g n i fi can t i ssu es i n test sampl e si ze an d preparati on , sci en ti fi c u n d erstan d i n g of d i sease processes, an d test
val i d ati on can be ci ted as l i m i tati on s of avai l abl e meth od s. For exam pl e, th e bi ol og i cal si g n i fi can ce of sol i d state
carci n og en esi s i s poorl y u n d erstood . I t i s expected th at on g oi n g sci en ti fi c an d m ed i cal ad van ces wi l l al ter ou r
u n d erstan d i n g of an d approach es to th ese i m portan t toxi ci ty test m eth od s. At th e ti m e th i s part of I SO 1 0993 was
prepared , th e test m eth od s proposed were th ose most acceptabl e. Sci en ti fi cal l y sou n d al tern ati ves to th e proposed
testi n g may be acceptabl e i n sofar as th ey ad d ress rel evan t m atters of safety assessm en t.
In th e sel ecti on of tests n eed ed to eval u ate a parti cu l ar med i cal d evi ce, th ere is no su bsti tu te for a carefu l
assessm en t of expected h u m an u ses an d poten ti al i n teracti on s of th e m ed i cal d evi ce wi th vari ou s bi ol og i cal system s.
Th ese con si d erati on s wi l l be parti cu l arl y i m portan t i n su ch areas as reprod u cti ve an d d evel opm en tal toxi col og y.
Th i s part of I SO 1 0993 presen ts test m eth od s for th e d etecti on of speci fi c bi ol og i cal h azard s, an d strateg i es for th e
sel ecti on of tests, wh ere appropri ate, th at wi l l assi st i n h azard i d en ti fi cati on . Testi n g i s n ot al ways n ecessary or
h el pfu l i n h azard i d en ti fi cati on bu t, wh ere i t i s appropri ate, i t i s i m portan t th at m axi m u m test sen si ti vi ty be ach i eved .
M ost tests i n cl u d ed in th i s part of I SO 1 0993 refer to G u i d el i n es for Testi n g of Ch em i cal s, prepared by th e
Org an i zati on for Econ om i c Cooperati on an d Devel opm en t (OECD).
Th e i n terpretati on of fi n d i n g s an d th ei r i mpl i cati on s for h u m an h eal th effects are beyon d th e scope of th i s part of I SO
1 0993. Becau se of th e mu l ti tu d e of possi bl e ou tcom es an d th e i mportan ce of factors su ch as exten t of exposu re,
speci es d i fferen ces, an d mech an i cal or ph ysi cal con si d erati on s, ri sk assessm en t h as to be perform ed on a case-by-
case basi s.
© 2003 Associ ati on for th e Ad van cem en t of M ed i cal I n stru m en tati on AN SI /AAM I /I SO 1 0993-3: 2003 ix

Am eri can N ati on al Stan dard AN SI /AAM I /I SO 1 0993-3: 2003/(R)201 3
Bi ol og i cal eval u ati on of m ed i cal d evi ces—
Part 3: Tests for g en otoxi ci ty, carci n og en i ci ty,
an d reprod u cti ve toxi ci ty
1 Scope
Th i s part of I SO 1 0993 speci fi es strateg i es for h azard i d en ti fi cati on an d tests on m ed i cal d evi ces for th e fol l owi n g
bi ol og i cal aspects:
— g en otoxi ci ty,
— carci n og en i ci ty, an d
— reprod u cti ve an d d evel opmen tal toxi ci ty.
Th i s part of I SO 1 0993 is appl i cabl e for eval u ati on of a med i cal d evi ce wh ose poten ti al for g en otoxi ci ty,
carci n og en i ci ty, or reprod u cti ve toxi ci ty h as been i d en ti fi ed .
N OTE —G u i d an ce on sel ecti on of tests i s provi d ed i n I SO 1 0993-1 .
2 N orm ati ve referen ces
Th e fol l owi n g referen ced d ocu m en ts are i n d i spen sabl e for th e appl i cati on of th i s d ocu m en t. For d ated referen ces,
on l y th e ed i ti on ci ted appl i es. For u n d ated referen ces, th e l atest ed i ti on of th e referen ced d ocu m en t (i n cl u d i n g an y
am en d m en ts) appl i es.
I SO 1 0993-1 : 1 997, Biological evaluation of medical devices—Part 1: Evaluation and testing
I SO 1 0993-2: 1 992, Biological evaluation of medical devices—Part 2: Animal welfare requirements
I SO 1 0993-6: 1 994, Biological evaluation of medical devices—Part 6: Tests for local effects after implantation
I SO 1 0993-1 2: 2002, Biological evaluation of medical devices—Part 12: Sample preparation and reference materials
I SO 1 0993-1 8, Biological evaluation of medical devices—Part 18: Chemical characterization of materials
1)
OECD 41 4 , Prenatal Development Toxicity Study
OECD 41 5, One-Generation Reproduction Toxicity Study
OECD 41 6, Two-Generation Reproduction Toxicity
OECD 421 , Reproduction/Developmental Toxicity Screening Test
OECD 451 , Carcinogenicity Studies
OECD 453, Combined Chronic Toxicity/Carcinogenicity Studies
OECD 471 , Bacterial Reverse Mutation Test
OECD 473, In vitro Mammalian Chromosome Aberration Test
OECD 476, In vitro Mammalian Cell Gene Mutation Test
1)
Org an i zati on for Econ om i c Cooperati on an d Devel opm en t.
© 2003 Associ ati on for th e Ad van cem en t of M ed i cal I n stru m en tati on AN SI /AAM I /I SO 1 0993-3: 2003 1

3 Term s an d defi n i ti on s
For th e pu rposes of th i s d ocu m en t, th e term s an d d efi n i ti on s g i ven i n I SO 1 0993-1 , I SO 1 0993-1 2, an d th e fol l owi n g
appl y.
3. 1 carci n og en i ci ty test: Test to d eterm i n e th e tu m ori g en i c poten ti al of m ed i cal d evi ces, materi al s, an d /or
extracts u si n g ei th er si n g l e or m u l ti pl e exposu res over a m aj or porti on of th e l i fe span of th e test an i m al .
N OTE —Th ese tests may be d esi g n ed to exam i n e both ch ron i c toxi ci ty an d tu m ori g en i ci ty i n a si n g l e experi m en tal stu d y. Wh en
ch ron i c toxi ci ty an d carci n og en i ci ty are eval u ated wi th i n a si n g l e stu d y, care i n stu d y d esi g n wi th em ph asi s on d ose sel ecti on sh ou l d
be exerci sed . Th i s wi l l h el p to en su re th at prem atu re m ortal i ty from ch ron i c/cu m u l ati ve toxi ci ty d oes n ot com promi se th e stati sti cal
eval u ati on of an i m al s th at su rvi ve u n ti l sch ed u l ed stu d y term i n ati on (i . e. n ormal l i fe-span ).
3. 2 en erg y-d eposi ti n g m ed i cal d evi ce: Devi ce i n ten d ed to exert i ts th erapeu ti c or d i ag n osti c effect by th e
d el i very of el ectromag n eti c rad i ati on , i on i zi n g rad i ati on , or u l trasou n d .
N OTE—Th i s d oes n ot i n cl u d e m ed i cal d evi ces th at d el i ver si m pl e el ectri cal cu rren t, su ch as el ectrocau tery m ed i cal d evi ces,
pacemakers, or fu n cti on al el ectri cal sti m u l ators.
3. 3 g en otoxi ci ty test: Test u si n g mam m al i an or n on -m amm al i an cel l s, bacteri a, yeasts, or fu n g i to d eterm i n e

wh eth er g en e m u tati on s, ch an g es i n ch rom osome stru ctu re, or oth er DN A or g en e ch an g es are cau sed by th e test
sam pl es.
N OTE —Th ese tests can i n cl u d e wh ol e an i m al s.
3. 4 maxi mu m tol erated d ose (M TD): M axi m u m d ose th at a test an i m al can tol erate wi th ou t an y ad verse
ph ysi cal effects.
3. 5 reprod u cti ve an d d evel opm en tal toxi ci ty test: Test to eval u ate th e poten ti al effects of test sam pl es on
reprod u cti ve fu n cti on , em bryon i c m orph ol og y (teratog en i ci ty), an d pren atal an d earl y postn atal d evel opm en t.
4 Gen otoxi ci ty tests
4. 1 Gen eral
Before a d eci si on to perform a g en otoxi ci ty test i s m ad e, I SO 1 0993-1 an d th e ch em i cal ch aracteri zati on of m ateri al s
(I SO 1 0993-1 8) sh al l be taken i n to accou n t. Th e rati on al e for a test prog ram , taki n g i n to con si d erati on al l rel evan t
factors, sh al l be d ocu m en ted .
I SO 1 0993-1 i n d i cates ci rcu m stan ces wh ere th e poten ti al for g en otoxi ci ty i s a rel evan t h azard for con si d erati on i n
an overal l bi ol og i cal safety eval u ati on (see I SO 1 0993-1 : 1 997, Tabl e 1 ). Testi n g for g en otoxi ci ty, h owever, i s n ot
n ecessary for m ed i cal d evi ces, an d com pon en ts th ereof, m ad e on l y from materi al s kn own to sh ow n o g en otoxi ci ty.
Testi n g for g en otoxi ci ty i s i n d i cated wh ere a revi ew of th e com posi ti on of th e m ateri al s reveal s th e possi bl e presen ce
i n th e fi n al m ed i cal d evi ce of com pou n d s th at m i g h t i n teract wi th g en eti c m ateri al , or wh en th e ch em i cal com posi ti on
of th e m ed i cal d evi ce i s u n kn own . I n su ch ci rcu m stan ces, th e g en otoxi c poten ti al of su spect ch em i cal com pon en ts
sh ou l d be assessed , beari n g i n mi n d th e poten ti al for syn erg y, i n preferen ce to carryi n g ou t g en otoxi ci ty tests on th e
materi al or med i cal d evi ce as a wh ol e.
Wh en th e g en otoxi ci ty of a m ed i cal d evi ce h as to be experi m en tal l y assessed , a seri es of in vitro tests sh al l be u sed .
Th i s seri es sh al l i n cl u d e ei th er two tests i f 4. 2. 1 . 2 i s perform ed , wh i ch u ses th e m ou se l ym ph om a assay i n corporati n g
col on y n u m ber an d si ze d eterm i n ati on , or th ree tests i f 4. 2. 1 . 1 i s perform ed . Wh en tests are performed , at l east two
tests, i n vesti g ati n g d i fferen t en d poi n ts, sh al l u se m amm al i an cel l s.
4. 2 Test strateg y
4. 2. 1 Gen otoxi ci ty testi n g sh al l be performed on th e basi s of an i n i ti al d eci si on to test i n accord an ce wi th ei th er

Opti on 1 (4. 2. 1 . 1 ) or Opti on 2 (4. 2. 1 . 2).
4. 2. 1 . 1 Opti on 1
a) a test for g en e m u tati on s i n bacteri a (OECD 471 ); an d
b) a test for g en e m u tati on s i n mam m al i an cel l s (OECD 476); an d
c) a test for cl astog en i ci ty i n m am m al i an cel l s (OECD 473).
2 © 2003 Associ ati on for th e Ad van cem en t of M ed i cal I n stru men tati on AN SI /AAM I /I SO 1 0993-3: 2003
4. 2 . 1 . 2 Opti on 2
a) a test for g en e m u tati on s i n bacteri a (OECD 471 ); an d
b) a test for g en e m u tati on s i n m am mal i an cel l s (OECD 476), speci fi cal l y a m ou se l ym ph oma assay i n corporati n g
col on y n u m ber an d si ze d eterm i n ati on i n ord er to cover both en d poi n ts (cl astog en i ci ty an d g en e mu tati on s).
4. 2 . 2 I f th e resu l ts of al l in vitro tests perform ed i n accord an ce wi th 4. 2. 1 are n eg ati ve, fu rth er g en otoxi ci ty testi n g
i n an i m al s i s n ot n orm al l y j u sti fi ed an d sh ou l d n ot be perform ed , i n th e i n terest of preven ti n g u n d u e u se of an i m al s.
In vivo testi n g sh al l be performed i n accord an ce wi th I SO 1 0993-2.
4. 2 . 3 I f an y of th e in vitro tests i s posi ti ve, ei th er in vivo m u tag en i ci ty tests sh al l be perform ed (see 4. 2. 4) or th e

presu m pti on sh al l be m ad e th at th e com pou n d i s m u tag en i c.
4. 2 . 4 An y in vivo test sh al l be ch osen on th e basi s of th e most appropri ate en d poi n t i d en ti fi ed by th e in vitro tests.
An attem pt sh al l be m ad e to d em on strate th at th e test su bstan ce h as reach ed th e targ et org an . I f th i s can n ot be
d emon strated , a secon d in vivo test i n an oth er targ et org an m ay be req u i red to veri fy th e l ack of in vivo g en otoxi ci ty.
In vivo tests com m on l y u sed are:
a) m i cron u cl eu s test i n rod en ts (OECD 474) or
b) m etaph ase an al ysi s i n rod en t bon e m arrow (OECD 475) or
c) u n sch ed u l ed DN A syn th esi s test wi th mam m al i an l i ver cel l s (OECD 486).
Th e d eci si on as to th e most appropri ate test system sh al l be j u sti fi ed an d d ocu m en ted .
4. 2 . 5 I f oth er in vivo test system s to i n vesti g ate g en otoxi ci ty are u sed i n ord er to obtai n ad d i ti on al i n form ati on ,
th e rati on al e for th i s sh al l be j u sti fi ed an d d ocu m en ted .
4. 3 S am p l e preparati on
4. 3 . 1 Wh ere g en otoxi ci ty tests are carri ed ou t on th e m ateri al or a m ed i cal d evi ce or as a wh ol e, sam pl e

preparati on sh al l be i n accord an ce wi th I SO 1 0993-1 2. Tests sh al l be perform ed on extracts, exag g erated extracts,
or th e i n d i vi d u al ch em i cal compou n d s of th e m ateri al /m ed i cal d evi ce. Th e h i g h est test con cen trati on sh al l be wi th i n
OECD g u i d el i n es. I f exag g erated extracti on con d i ti on s are u sed , care sh al l be taken th at th i s d oes n ot al ter th e
ch emi cal ch aracteri sti cs.
4. 3 . 2 An appropri ate sol ven t sh al l be ch osen on th e basi s of i ts com pati bi l i ty wi th th e test system an d i ts abi l i ty to
m axi m i ze extracti on of th e m ateri al or m ed i cal d evi ce. Th e rati on al e for th e ch oi ce of sol ven t sh al l be d ocu m en ted .
4. 3 . 3 Wh ere rel evan t, two appropri ate extractan ts sh al l be u sed , on e of wh i ch i s a pol ar sol ven t, th e secon d a
n on -pol ar sol ven t or l i q u i d appropri ate to th e n atu re an d u se of th e m ed i cal d evi ce, both of wh i ch are compati bl e wi th
th e test system .
4. 4 Tes t m eth od s
4. 4. 1 In vitro g en otoxi ci ty tes ts
Test meth od s for in vitro g en otoxi ci ty tests sh al l be ch osen from th e OECD G u i d el i n es for Testi n g of Ch em i cal s.
Preferred test m eth od s are: OECD 471 , OECD 473, OECD 476, OECD 479, an d OECD 482. I t m ay be n ecessary
to con si d er, i n th e d esi g n an d sel ecti on of tests, th at a n u m ber of m ateri al s or su bstan ces can i n fl u en ce th e test,
e. g . an ti bi oti cs an d an ti septi cs. I f th i s i s rel evant, th e rati on al e for th e d eci si on sh al l be d ocu m en ted .
4. 4. 2 In vivo g en otoxi ci ty tes ts
Test meth od s for in vivo g en otoxi ci ty tests sh al l be ch osen from th e OECD G u i d el i n es for Testi n g of Ch em i cal s.
Preferred test meth od s are: OECD 474, OECD 475, OECD 478, OECD 483, OECD 484, OECD 485, an d OECD 486.
N OTE —Recen tl y, tran sg en i c an i mal test system s h ave been d evel oped for g en otoxi ci ty testi n g . Th ese tests m ay prove val u abl e for
med i cal d evi ce testi n g , bu t th ei r u se h as n ot been val i d ated at th e ti m e of pu bl i cati on of th i s part of I SO 1 0993. Referen ces on test
system s are g i ven i n th e bi bl i og raph y for tran sg en i c an i mal s.

5 C arci n og en i ci ty tes ts
5. 1 G en eral
Before a d eci si on to perform a carci n og en i ci ty test i s m ad e, I SO 1 0993-1 an d I SO 1 0993-1 8 sh al l be taken i n to

accou n t. Th e d eci si on to perform a test sh al l be j u sti fi ed on th e basi s of an assessm en t of th e ri sk of carci n og en esi s
ari si n g from th e u se of th e med i cal d evi ce. Carci n og en i ci ty testi n g sh al l n ot be perform ed wh en ri sks can be
ad eq u atel y assessed or m an ag ed wi th ou t g en erati n g n ew carci n og en i ci ty test d ata.
N OTE —Th ere are su i tabl e in vitro cel l tran sformati on system s th at m ay be u sed for carci n og en i ci ty prescreen i n g . Cel l
tran sform ati on tests h ave so far n ot been d escri bed i n I n tern ati on al Stan d ard s. Ad d i ti on al i n formati on on cel l tran sformati on test
system s are g i ven i n An n ex A.
5. 2 Tes t s trateg y
5. 2 . 1 I n th e absen ce of evi d en ce to ru l e ou t carci n og en i c ri sks, si tu ati on s i n wh i ch th e n eed for carci n og en i ci ty

testi n g sh al l be con si d ered m ay i n cl u d e th e fol l owi n g :
a) resorbabl e m ateri al s an d m ed i cal d evi ces for wh i ch th e resorpti on ti m e i s g reater th an 30 d ays, u n l ess th ere are
si g n i fi can t an d ad eq u ate d ata on h u m an u se or exposu re;
b) m ateri al s an d m ed i cal d evi ces i n trod u ced i n th e bod y an d /or i ts cavi ti es wi th a perm an en t or cu m u l ati ve con tact
of g reater th an 30 d ays, except wh en si g n i fi can t an d ad eq u ate h u m an -u se h i story i s avai l abl e.
Carci n og en i ci ty testi n g of g en otoxi c m ateri al s i s n ot sci en ti fi cal l y j u sti fi ed . For g en otoxi c m ateri al s, a carci n og en i c
h azard sh al l be presu m ed an d th e ri sk man ag ed accord i n g l y.
5. 2 . 2 Wh en i n accord an ce wi th I SO 1 0993-1 , ch ron i c toxi ci ty an d carci n og en i ci ty h ave been con si d ered , an d i t

i s d eterm i n ed th at testi n g i s n ecessary, tests sh al l be perform ed i n accord an ce wi th OECD 453, i f possi bl e.
5. 2 . 3 Wh en in accord an ce wi th I SO 1 0993-1 , on l y a carci n og en i ci ty stu d y h as been con si d ered , an d it is

d eterm i n ed th at testi n g i s n ecessary, tests sh al l be perform ed i n accord an ce wi th OECD 451 .
5. 2 . 4 On e an i m al speci es i s su ffi ci en t for testi n g m ed i cal d evi ces. Th e ch oi ce of speci es sh al l be j u sti fi ed an d

d ocu m en ted .
N OTE —Recen tl y, tran sg en i c an i m al tests h ave been d evel oped for carci n og en i ci ty testi n g , bu t th ey h ave n ot been val i d ated for
med i cal d evi ces at th e ti m e of pu bl i cati on of th i s part of I SO 1 0993. Referen ces on test systems are g i ven i n th e bi bl i og raph y for
tran sg en i c an i mal tests as al tern ati ves to l i feti m e carci n og en i ci ty tests.
5. 3 S am pl e p rep arati on
Sam pl e preparati on sh al l be i n accord an ce wi th I SO 1 0993-1 2. Wh en ever possi bl e, th e med i cal d evi ce sh al l be

tested i n a form represen tati ve of i ts “read y-to-u se” state.
5. 4. 1 I f carci n og en i ci ty tests are n ecessary as part of an eval u ati on of bi ol og i cal safety, th ese stu d i es sh al l be
perform ed wi th d efi n ed ch em i cal s or ch aracteri zed extracts of m ed i cal d evi ces. Th e perform an ce of i m pl an tati on
stu d i es (see An n ex C) sh al l be j u sti fi ed , an d th e rol e i n th e eval u ati on of h u m an ri sk sh al l be d escri bed an d
d ocu m en ted .
5. 4. 2 I f an i m pl an tati on stu d y i s to be perform ed , con si d erati on sh al l be g i ven to th e cl i n i cal u se of th e m ed i cal

d evi ce i n sel ecti n g th e i mpl an t si te.
5. 4. 3 I f testi n g of an extract i s con si d ered rel evan t, th e carci n og en i ci ty tests sh al l be performed i n accord an ce wi th
OECD 451 or OECD 453.
5. 4. 4 Ti ssu es eval u ated sh al l i n cl u d e rel evan t ti ssu es from th e l i st i n d i cated i n OECD 451 or OECD 453, as wel l
as th e i m pl an tati on an d ad j acen t ti ssu es.
6 Reprod u cti ve an d d e vel opm en tal toxi ci ty tes ts
6. 1 G en eral
6. 1 . 1 Before a d eci si on to perform reprod u cti ve an d d evel opm en tal toxi ci ty tests i s m ad e, I SO 1 0993-1 an d
I SO/DI S 1 0993-1 8 sh al l be taken i n to accou n t. Th e d eci si on to perform a test sh al l be j u sti fi ed on th e basi s of an
assessmen t of th e ri sk of reprod u cti ve an d d evel opm en tal toxi ci ty ari si n g from th e u se of th e med i cal d evi ce.
6. 1 . 2 Th ere i s n o n eed for th e reprod u cti ve toxi ci ty testi n g of resorbabl e m ed i cal d evi ces or m ed i cal d evi ces
con tai n i n g l each abl e su bstan ces i f th ere are ad eq u ate an d reassu ri n g d ata from absorpti on , metabol i sm , an d
d i stri bu ti on stu d i es or on th e l ack of th e reprod u cti ve toxi ci ty of al l com pon en ts i d en ti fi ed i n extracts of m ateri al s or
med i cal d evi ces.
6. 1 . 3 Reprod u cti ve an d d evel opm en tal toxi ci ty testi n g is n ot req u i red wh ere an acceptabl e bi ol og i cal ri sk
assessm en t of th e m ed i cal d evi ce takes i n to accou n t th e fact th at th e ri sk of reprod u cti ve an d d evel opm en tal toxi ci ty
h as been ru l ed ou t.
6. 2 Tes t s trateg y
I n th e absen ce of evi d en ce to ru l e ou t reprod u cti ve/d evel opmen tal ri sks, reprod u cti ve/d evel opm en tal tests sh al l be
con si d ered . Thi s m ay i n cl u d e tests on th e fol l owi n g :
a) prol on g ed - or perm an en t-con tact d evi ces l i kel y to com e i n to d i rect con tact wi th reprod u cti ve ti ssu es or th e
em bryo/fetu s;
b) en erg y-d eposi ti n g m ed i cal d evi ces;
c) resorbabl e materi al s or l each abl e su bstan ces.
I f testi n g i s req u i red , th i s sh al l start wi th OECD 421 i n ord er to provi d e i n i ti al i n formati on on possi bl e effects on
reprod u cti on an d /or d evel opm en t. Posi ti ve resu l ts wi th th ese tests are u sefu l for i n i ti al h azard assessmen t an d
con tri bu te to d eci si on s wi th respect to th e n ecessi ty for an d ti mi n g of ad d i ti on al tests.
I f ad d i ti on al tests are con si d ered n ecessary, th ey sh al l be perform ed i n accord an ce wi th OECD 41 4, OECD 41 5, or

OECD 41 6, as appropri ate.
6. 3 S am pl e p rep arati on
6. 3 . 1 Sam pl e preparati on sh al l be i n accord an ce wi th I SO 1 0993-1 2. Wh en ever possi bl e, th e m ed i cal d evi ce

sh al l be tested i n a form represen tati ve of i ts “read y-to-u se” state.
6. 3 . 2 In th e case of en erg y-d eposi ti n g m ed i cal d evi ces, wh ol e-bod y exposu re of th e an i m al s i s appropri ate.
A m u l ti pl e of th e pred i cted h u m an exposu re to th e reprod u cti ve org an s sh al l be appl i ed .
6. 3 . 3 Th e h i g h est d ose u sed i n th e an i m al s i s ei th er th e m axi m u m tol erated d ose or th at l i m i ted by th e ph ysi cal
con strai n ts of th e an i mal m od el . Th i s d ose sh al l be expressed as a m u l ti pl e of th e esti m ated m axi m u m h u m an
exposu re (i n m ass an d /or su rface area of d ose per ki l og ram of su bj ect).
In vivo testi n g sh al l be perform ed i n accord an ce wi th I SO 1 0993-2.
6. 4. 1 Assessmen t of effects on th e fi rst g en erati on (F1 ) or even secon d g en erati on (F2) sh al l be mad e in
accord an ce wi th OECD 41 4, OECD 41 5 or OECD 41 6, an d OECD 421 . As th e OECD g u i d el i n es were n ot i n ten d ed
for m ed i cal d evi ces, th e fol l owi n g m od i fi cati on s sh al l be con si d ered :
⎯ d ose (i n th e case of en erg y-d eposi ti n g m ed i cal d evi ces);
⎯ rou te of appl i cati on (i m pl an t, paren teral , oth er);
⎯ extracti on med i a (aq u eou s an d n on -aq u eou s extracts);
⎯ exposu re ti m e (el evated l evel s i n bl ood d u ri n g org an og en esi s, wh en possi bl e).
N OTE —Depen d i n g on i n ten d ed h u m an u se an d m ateri al ch aracteri sti cs, peri -/post-n atal stu d i es m ay be i n d i cated .

6. 4. 2 I f i n form ati on d eri ved from oth er tests i n d i cates poten ti al effects on th e m al e reprod u cti on system , th en
appropri ate tests for mal e reprod u cti ve toxi ci ty sh al l be con d u cted .
N OTE —Recen tl y, in vitro reprod u cti ve test system s h ave been d evel oped . Th ey can be u sefu l as a prescreen i n g test meth od
for reprod u cti ve an d d evel opmen tal toxi ci ty. Referen ces to in vitro reprod u cti ve test system s are i n cl u d ed i n th e bi bl i og raph y for
reprod u cti ve/d evel opm en tal toxi ci ty testi n g .
7 Te s t report
7. 1 Th e test report sh al l i n cl u d e at l east th e fol l owi n g d etai l s, wh ere rel evan t:
a) d escri pti on of m ateri al an d /or m ed i cal d evi ce, i n cl u d i n g i n ten d ed u se (e. g . ch em i cal com posi ti on , processi n g ,
con d i ti on i n g , an d su rface treatm en t);
b) d escri pti on an d j u sti fi cati on of test m eth od s, test con d i ti on s, test m ateri al s, an d test proced u res;
c) d escri pti on of an al yti cal m eth od s, i n cl u d i n g q u an ti fi cati on l i mi ts;
d) statem en t of com pl i an ce to appropri ate g ood l aboratory practi ces;
e) test resu l ts, i n cl u d i n g su m m ary;
f) stati sti cal m eth od s;
g) i n terpretati on an d d i scu ssi on of resu l ts.
7. 2 Fu rth er d etai l s as speci fi ed i n th e rel evan t OECD g u i d el i n es sh al l be i n cl u d ed i n th e test report, i f appl i cabl e.
Annex A
(i n form ati ve)
Cell transformation test system
Cel l tran sform ati on test system s m ay be u sed for carci n og en i ci ty prescreen i n g .
G u i d an ce i s g i ven i n [1 2] for in vitro cel l tran sform ati on tests. Fu rth er referen ces on cel l tran sform ati on test system s
are g i ven i n th e bi bl i og raph y for cel l tran sform ati on assays.
Th ere i s al so som e evi d en ce th at two-step cel l tran sform ati on assays can d etect carci n og en s wh i ch are n on -
g en otoxi c, bu t at th i s ti m e i t i s n ot possi bl e to con cl u d e th at al l n on -g en otoxi c carci n og en s can be d etected by cel l
tran sform ati on assays. Th erefore, cel l tran sformati on test system s can n ot be u sed as an al tern ati ve to l i feti m e
carci n og en i ci ty stu d i es i n at l east on e appropri ate rod en t speci es.

An n ex B
(i n form ati ve)
Rati on al e of tes t s ys tem s
B. 1 G en otoxi ci ty tes ts
Th e pri m ary fu n cti on of g en otoxi ci ty tests i s to i n vesti g ate, u si n g test cel l s or org an i sm s, th e poten ti al of prod u cts
to i n d u ce g en eti c ch an g es i n m an th at m ay be tran sm i tted vi a th e g erm cel l s to fu tu re g en erati on s. S ci en ti fi c d ata
g en eral l y su pport th e h ypoth esi s th at D N A d am ag e i n som ati c cel l s i s a cri ti cal even t i n th e i n i ti ati on of can cer.
S u ch d am ag e can resu l t i n m u tati on s, an d tests to d etect g en otoxi c acti vi ty m ay al so i d en ti fy ch em i cal s th at h ave
th e poten ti al to l ead to carci n og en esi s. Th u s, som e of th e tests are u sefu l for th e i n vesti g ati on of pu tati ve
carci n og en i c acti vi ty.
Wh i l e i n cl assi cal toxi col og y tests several perti n en t param eters or en d poi n ts can be observed wi th i n on e experi m en tal
d esi g n , th e sam e i s n ot tru e for g en eti c toxi col og y. Th e d i versi ty of th e g en eti c en d poi n ts u su al l y precl u d es th e
d etecti on of m ore th an on e of th em i n a si n g l e test system .
Approxi matel y fi fteen d i fferen t tests are ci ted i n test g u i d el i n es. Th e sel ecti on of th e m ost appropri ate of th ese to m eet
a parti cu l ar req u i rem en t i s g overn ed by a n u m ber of factors. Th ese i n cl u d e th e type of g en eti c ch an g e i t i s req u i red to
d etect, or th e m etabol i c capabi l i ty of th e test system.
I t m u st be emph asi zed th at th ere i s n o i n tern ati on al ag reemen t on th e best combi n ati on of tests for a parti cu l ar
pu rpose, th ou g h th ere h ave been attem pts to h armon i ze th e sel ecti on of th e m ost appropri ate tests. I t m ay al so be
h el pfu l to n ote th at th ere are oth er m u tag en i ci ty tests i n u se or i n d evel opm en t wh i ch , al th ou g h wi th ou t an OECD
Gu i d el i n e, m ay al so be u sefu l . Th e exi sten ce of th e I CH /S2B ag reem en t for ph arm aceu ti cal s sh ou l d be n oted .
Ch em i cal s th at i n teract wi th DN A prod u ce l esi on s wh i ch , after th e i n fl u en ce of vari ou s repai r processes, m ay l ead to

g en eti c ch an g es at th e g en e l evel , e. g . g en e or poi n t mu tati on s, sm al l d el eti on s, mi toti c recom bi n ati on , or vari ou s
mi croscopi cal l y vi si bl e ch rom osom e ch an g es, an d tests are avai l abl e to i n vesti gate each of th ese even ts.
Cu rren t sh ort-term tests can n ot, of cou rse, m i mi c al l th e stages i n th e carci n ogen i c process an d are freq u en tl y
assu med to d etect on l y th e even t l ead i n g to th e i n i ti ati on ph ase, i . e. th e abi l i ty to i n d u ce a m u tag en i c or cl astog en i c
DN A l esi on . Th e m ai n val u e of th ese proced u res, th erefore, l i es i n th ei r abi l i ty to i d en ti fy su bstan ces th at may, u n d er
certai n exposu re con d i ti on s, ei th er cau se can cer by a pred om i n an tl y g en otoxi c m ech an i sm or i n d u ce th e i n i ti al ph ase
of th e carci n og en i c process. I t i s apparen t, from th e com pl exi ty of th e carci n og en i c process com pared wi th th e
rel ati ve si m pl i ci ty of sh ort-term tests, th at, al th ou g h th ey provi d e u sefu l q u al i tati ve i n form ati on , con si d erabl e cau ti on i s
req u i red i n th ei r i n terpretati on i n term s of carci n og en i c acti vi ty.
Si n ce n o si n g l e test h as proved capabl e of d etecti n g m am m al i an m u tag en s an d carci n ogen s wi th an acceptabl e l evel

of preci si on an d reprod u ci bi l i ty, i t i s u su al sci en ti fi c practi ce to appl y th ese tests i n "batteri es. " I n i ti al i n formati on on
th e m u tag en i ci ty of a su bstan ce can be obtai n ed u si n g tests th at m easu re g en e m u tati on s an d ch rom osom al
d am ag e. Becau se separate proced u res are req u i red to i n vesti g ate th ese en d poi n ts, a battery of tests i s n eed ed .
B. 2 C arci n og e n i ci ty s tu d i es
Th e obj ecti ve of a l on g -term carci n og en i ci ty stu d y i s to observe test an i m al s, for a maj or porti on of th ei r l i fe span ,
for th e d evel opmen t of n eopl asti c l esi on s, d u ri n g or after exposu re to vari ou s d oses of a test su bstan ce by an
appropri ate rou te. Su ch a test req u i res carefu l pl an n i n g an d d ocu m en tati on of th e experi men tal d esi g n (see
An n ex C), a h i g h q u al i ty of path ol og y, an d u n bi ased stati sti cal an al ysi s.
B. 3 Reprod u cti ve/d e vel opm e n tal toxi ci ty tes ts
Reprod u cti ve toxi ci ty tests cover th e areas of reprod u cti on , ferti l i ty, an d teratog en i ci ty. I t h as been fou n d th at m an y
su bstan ces can affect ferti l i ty an d reprod u cti on , often i n an i n si d i ou s m an n er wi th ou t oth er si gn s of toxi ci ty. Ferti l i ty
can be affected i n m al es an d fem al es, an d effects can ran g e from sl i g h tl y d ecreased reprod u cti ve capabi l i ty to
com pl ete steri l i ty.
Teratog en i ci ty d eal s wi th th e ad verse effects of a su bstan ce on th e d evel opi n g em bryo an d fetu s. Reprod u cti ve
toxi ci ty h as an i mportan t beari n g on th e h eal th of m an ki n d . Test tech n i q u es are d evel opi n g an d th e con cept of
com bi n ed tests, coveri n g al l aspects of reprod u cti ve toxi col og y, appears promi si n g .
An n ex C
(i n form ati ve)
Rol e of i m pl an tati on carci n og en i ci ty s tu d i es
C. 1 G en e ral
Tu mors i n d u ced by i m pl an ts are wel l kn own i n experi m en ts u si n g rats. Th i s ph en om en on i s cal l ed "forei g n bod y
carci n og en esi s" or "sol i d state carci n og en esi s. " Th e ph en om en on i s su m m ari zed as fol l ows.
Tu m ors u su al l y d evel op arou n d or n ear an i m pl an t wi th a freq u en cy th at i s d epen d en t on several factors:
a) th e si ze of th e i m pl an t (l arg e i m pl an ts g en eral l y prod u ce m ore sarcom as th an sm al l on es);
b) th ei r form (d i scs are reported to be am on g th e m ost effi ci en t);
c) th ei r sm ooth n ess (th ose wi th rou g h su rfaces are l ess carci n og en i c th an th ose wi th sm ooth su rfaces);
d) th e con ti n u i ty of th e su rface area (th e l arg er th e h ol es or pores i n th e i m pl an t, th e l ower th e tu m or i n ci d en ce);
e) for certai n materi al s, th ei r th i ckn ess (th i cker i m pl an ts prod u ce more sarcom as);
f) th e l en g th of ti m e th e i m pl an t rem ai n s i n th e ti ssu e.
Th e same m ateri al th at prod u ces tu m ors as a fi l m or sh eet wi l l , for th e m ost part, prod u ce fewer or n o tu mors wh en
[33] , [34]
i m pl an ted as a powd er, a th read , or a porou s m ateri al .
On th e oth er h an d , man y reports i n d i cate a d i fferen ce of i n ci d en ce of tu m or form ati on am on g d i fferen t m ateri al s of

si m i l ar sh ape an d si ze u si n g th e sam e an i m al experi men tal protocol .
[35]
M ech an i sti c u n d erstan d i n g s were su m m ari zed i n an I ARC M on og raph .
C. 2 Th e proce s s an d rati on al e of d eci s i on
U n d er th ese ci rcu mstan ces, th e Worki n g G rou p h as recon si d ered th e cu rren t g u i d el i n e i n I SO 1 0993-3 on th e d esi g n
of carci n ogen i ci ty stu d i es.
Th e Worki n g G rou p were presen ted wi th d ata obtai n ed u si n g a speci fi ed protocol i n cl u d i n g a d efi n ed an d con si sten t
[36]
sh ape for al l i m pl an ted m ateri al s. Th i s protocol i n vol ved 2 year su bcu tan eou s i m pl an tati on of a fi l m i m pl an t of
d i m en si on s 1 0 m m × 20 m m × (0. 5 m m to 1 . 0 mm ) in 30 to 50 m al e Wi star or F344 rats at a n u m ber of
establ i sh m en ts. Th ese d ata d em on strated a si g n i fi can t i n crease i n th e n u m ber of tu m ors d etected i n test an i m al s
com pared to sh am -operated con trol s for al l th e m ateri al s tested , i n cl u d i n g n omi n al n eg ati ve con trol s. Th e proporti on
of test an i m al s wi th tu m ors ran g ed from 7 % for si l i con e to 70 % for pol yeth yl en e, h owever th ere was on l y a l i ttl e
vari ati on (5 %, 7 %, an d 1 0 % ) wh en stu d i es were repeated wi th si l i con e. Th e g rou p al so revi ewed a presen tati on
on a n ew h ypoth esi s su g g esti n g th at sol i d state carci n og en esi s may be rel ated to i n terferen ce of g ap-j u n cti on al
[37]
i n tercel l u l ar com mu n i cati on cau sed by cel l /materi al i n teracti on s. Th e g rou p con si d ered th i s th eory prom i si n g bu t
con si d ered i ts rel evan ce to carci n og en i c ri sk to h u m an s as am bi g u ou s.
Du ri n g th e d i scu ssi on , represen tati ves from Eu ropean , J apan ese, an d U . S. reg u l atory bod i es ag reed th at n o d eci si on
on carci n og en i c ri sk h as been m ad e on th e basi s of sol i d state carci n og en esi s al on e. I n th e few exam pl es kn own ,
wh ere d eci si on s on carci n og en i c ri sk were m ad e u si n g sol i d state carci n og en esi s resu l ts, th ere h ad al ways been
su pporti n g d ata, su ch as posi ti ve m u tagen i ci ty d ata.
Th e con d u ct of carci n og en i ci ty stu d i es by i m pl an tati on req u i res su rg i cal l y i n vasi ve proced u res on both test an d
con trol (sh am -operated ) an i mal s. Th u s th ere i s a si g n i fi can t an i m al wel fare cost i n con d u cti n g su ch a stu d y. I n
con si d eri n g th e m eth od ol og y for carci n og en i ci ty stu d i es wh i l e u n d ertaki n g th e revi si on of th i s part of I SO 1 0993,
th e Worki n g G rou p con si d ered th at th ey cou l d n o l on g er j u sti fy req u i ri n g carci n og en i ci ty stu d i es to be performed by
i m pl an tati on u n d er th e presen t am bi g u ou s rel evan ce to h u m an ri sk. Th e su pporti n g rati on al e was th e l ack of an y
cl ear rol e for th ese i m pl an tati on stu d i es i n d eci si on s affecti n g th e eval u ati on of bi ol og i cal safety com bi n ed wi th th e
marked an i m al wel fare cost.
I f carci n ogen i ci ty stu d i es are d eem ed n ecessary (see 5. 4. 1 ), h owever, th e m eth od provi d ed i n C. 3 m ay assi st i n th e
i n terpretati on of carci n og en i ci ty stu d i es perform ed by i m pl an tati on . I f su ch stu d i es are perform ed , th e n eed for th e
stu d y d esi g n sh ou l d be j u sti fi ed an d i ts rol e i n th e eval u ati on of h u man ri sk d escri bed .

C. 3 C arci n og en i ci ty s tu d i es perform ed as i m pl an tati on tes ts
I f th i s opti on al proced u re i s performed , th e fol l owi n g protocol sh al l be fol l owed .
Wh i l e a si n g l e m axi mu m i m pl an tabl e d ose (M I D) g rou p m ay be su ffi ci en t, two d ose g rou ps i n cl u d i n g th e M I D an d

a fracti on th ereof (u su al l y on e-h al f of th e M I D) are recom m en d ed . Th e n eg ati ve con trol g rou p wi l l g en eral l y recei ve
a com parabl e sh ape an d form of a cl i n i cal l y acceptabl e m ateri al or referen ce con trol materi al wh ose l ack of
carci n og en i c poten ti al h as been d ocu m en ted , e. g . pol yeth yl en e i m pl an ts.
I n carci n og en i ci ty tests on rod en ts, th e M I D of a m ateri al or m ed i cal d evi ce sh al l be appl i ed . I f possi bl e, th i s d ose
sh al l be expressed as a mu l ti pl e of th e worst-case h u m an exposu re, i n mi l l i g rams per ki l og ram .
Th e m ass an d /or su rface area th at d eterm i n es th e i m pl an t d ose sh al l exceed th e expected cl i n i cal exposu re.
Th e rati on al e for d ose sel ecti on sh al l be d ocu m en ted . Wh en appropri ate, a su i tabl y form ed i m pl an t i n accord an ce
wi th I SO 1 0 993-6 sh al l be m ad e of th e test m ateri al (s), wi th appropri ate con si d erati on bei n g g i ven for th e
possi bi l i ty of i n d u ci n g sol i d state carci n og en i ci ty (O ppen h ei m er effect; see bi bl i og raph y for g en otoxi ci ty an d
[3 1 ]
carci n og en i ci ty testi n g ).
10 © 2003 Associ ati on for th e Ad van cem en t of M ed i cal I n stru m en tati on AN SI /AAM I /I SO 1 0993-3: 2003
Bibliography
General bibliography
[1 ] OE CD 474, Mammalian Erythrocyte Micronucleus Test
[2 ] OE CD 475, Mammalian Bone Marrow Chromosome Aberration Test
[3 ] OE CD 478, Genetic Toxicology—Rodent Dominant Lethal Test
[4 ] OE CD 479, Genetic Toxicology—In Vitro Sister Chromatid Exchange Assay in Mammalian Cells
[5 ] OE CD 480, Genetic Toxicology—Saccharomyces cerevisiae ⎯ Gene Mutation Assay
[6 ] OE CD 481 , Genetic Toxicology—Saccharomyces cerevisiae ⎯ Miotic Recombination Assay
[7 ] OE CD 482 , Genetic Toxicology—DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells
In vitro
[8 ] OE CD 483, Mammalian Spermatogonial Chromosome Aberration Test
[9 ] OE CD 484, Genetic Toxicology—Mouse Spot Test
[1 0 ] OE CD 485, Genetic Toxicology—Mouse Heritable Translocation Assay
[1 1 ] OE CD 486, Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells In Vivo
[1 2 ] O ffi ci a l J ou rn a l of th e E u rop e a n C om m u n i ti es , L 1 3 3 /7 3 , M ay 1 988, con ce rn i n g in vitro ce l l tra n s form a ti on
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m ed i cal d evi ces — Part 3 :

Tests for g en otoxi ci ty,

reprod u cti ve toxi ci ty

Copyright Association for the Advancement of Medical Instrumentation

device as a fume of reference for device evaluation. S imilarly, even j udgment.

Copyright Association for the Advancement of Medical Instrumentation

B i ol og i cal eval u ati on of m ed i cal d evi ce s —P art 3 :

Tes ts for g en otoxi ci ty, carci n og en i ci ty, an d

reprod u cti ve toxi ci ty

Approved 8 October 2003 by

Approved 23 October 2003 an d reaffirmed 26 N ovember 201 3 by

carci n og en i ci ty, an d reprod u cti ve an d d evel opm en tal toxi ci ty.

Copyright Association for the Advancement of Medical Instrumentation

Copyright Association for the Advancement of Medical Instrumentation

G l ossary of eq u i val en t stan d ard s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i v

Com mi ttee represen tati on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

Backg rou n d of AN SI /AAM I ad opti on of I SO 1 0993-3: 2003 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi i

2 N orm ati ve referen ces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

6 Reprod u cti ve an d d evel opm en tal toxi ci ty tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

An n ex A (i n form ati ve) Cel l tran sform ati on test system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

An n ex B (i n form ati ve) Rati on al e of test system s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

An n ex C (i n form ati ve) Rol e of i m pl an tati on carci n og en i ci ty stu d i es . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Copyright Association for the Advancement of Medical Instrumentation

I n tern ati on al d es i g n ati on U . S . d es i g n ati on E q u i val en cy

IEC 60601 -1 -2:2001 ANSI/AAMI/IEC 60601 -1 -2:2001 Identical

iv © 2003 Association for the Advancement of Medical Instrumentation  ANSI/AAMI/ISO 1 0993-3:2003

I SO 1 1 1 38-1 : 1 994 AN SI /AAM I ST59: 1 999 M aj or tech n i cal vari ati on s

I SO 1 1 1 38-2: 1 994 AN SI /AAM I ST21 : 1 999 M aj or tech n i cal vari ati on s

I SO 1 1 1 38-3: 1 995 AN SI /AAM I ST1 9: 1 999 M aj or tech n i cal vari ati on s

I SO TS 1 1 1 39: 2001 AN SI /AAM I /I SO 1 1 1 39: 2002 I d en ti cal

I SO 1 1 1 40-1 : 1 995 an d AN SI /AAM I ST60: 1 996 M aj or tech n i cal vari ati on s

I SO 1 1 607: 2003 AN SI /AAM I /I SO 1 1 607: 2000 I d en ti cal

I SO 1 1 737-1 : 1 995 AN SI /AAM I /I SO 1 1 737-1 : 1 995 I d en ti cal

I SO 1 1 737-2: 1 998 AN SI /AAM I /I SO 1 1 737-2: 1 998 I d en ti cal

I SO TR 1 3409: 1 996 AAM I /I SO TI R1 3409: 1 996 I d en ti cal

I SO 1 3485: 2003 AN SI /AAM I /I SO 1 3485: 2003 I d en ti cal

I SO 1 3488: 1 996 AN SI /AAM I /I SO 1 3488: 1 996 I d en ti cal

I SO 1 41 55-1 : 2003 AN SI /AAM I /I SO 1 41 55-1 : 2003 I d en ti cal

I SO 1 41 55-2: 2003 AN SI /AAM I /I SO 1 41 55-2: 2003 I d en ti cal

I SO 1 41 60: 1 998 AN SI /AAM I /I SO 1 41 60: 1 998 I d en ti cal

I SO 1 41 61 : 2000 AN SI /AAM I /I SO 1 41 61 : 2000 I d en ti cal

I SO 1 4937: 2000 AN SI /AAM I /I SO 1 4937: 2000 I d en ti cal

I SO 1 4969: 1 999 AN SI /AAM I /I SO 1 4969: 1 999 I d en ti cal

I SO 1 4971 : 2000 an d A1 : 2003 AN SI /AAM I /I SO 1 4971 : 2000 an d A1 : 2003 I d en ti cal

I SO 1 5223: 2000 AN SI /AAM I /I SO 1 5223: 2000 I d en ti cal

I SO 1 5223/A1 : 2002 AN SI /AAM I /I SO 1 5223: 2000/A1 : 2001 I d en ti cal

I SO 1 5225: 2000 AN SI /AAM I /I SO 1 5225: 2000 I d en ti cal

I SO 1 5674: 2001 AN SI /AAM I /I SO 1 5674: 2001 I d en ti cal

I SO 1 5675: 2001 AN SI /AAM I /I SO 1 5675: 2001 I d en ti cal

I SO TS 1 5843: 2000 AN SI /AAM I /I SO TI R1 5843: 2000 I d en ti cal

I SO TR 1 5844: 1 998 AAM I /I SO TI R1 5844: 1 998 I d en ti cal

I SO TR 1 61 42: 1 999 AN SI /AAM I /I SO TI R1 61 42: 2000 I d en ti cal

I SO 25539-1 : 2003 AN SI /AAM I /I SO 25539-1 : 2003 I d en ti cal

Copyright Association for the Advancement of Medical Instrumentation

As s oci ati on for th e Ad van cem en t of M ed i cal I n s tru m en tati on

B i ol og i cal E val u ati on C om m i ttee

Worki n g G rou phad the following members:

vi © 2003 Association for the Advancement of Medical Instrumentation  ANSI/AAMI/ISO 1 0993-3:2003

Th i s ed i ti on of I SO 1 0993-3 i s d i fferen t from th e 1 992 ed i ti on i n th at i t ch an g es th e recom m en d ati on s for sam pl e

Copyright Association for the Advancement of Medical Instrumentation

⎯ Part 1 : Evaluation and testing

⎯ Part 2: Animal welfare requirements

iv © 2003 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 1 0993-3:2003

vi © 2003 Association for the Advancement of Medical Instrumentation ANSI/AAMI/ISO 1 0993-3:2003