Iso 10993 11 2017 PDF

INTERNATIONAL ISO
STANDARD 10993-11
Third edition
2017-09
Biological evaluation of medical

devices —
Part 11:
Tests for systemic toxicity
Évaluation biologique des dispositifs médicaux —
Partie 11: Essais de toxicité systémique
Reference number
ISO 10993-11:2017(E)
© ISO 2017
ISO 10993-11:2017(E)
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ii © ISO 2017 – All rights reserved

ISO 1 0993 -1 1 : 2 0 1 7(E)
Contents Page
Foreword .................................................. ................................................... ................................................... ................................................... ............................... v
Introduction .................................................. ................................................... ................................................... ................................................... ..................... vi
1 Scope .................................................. ................................................... ................................................... ................................................... ...................... 1
2 Normative references .................................................. ................................................... ................................................... .............................. 1
3 Terms and definitions .................................................. ................................................... ................................................... ............................. 1

4 General considerations .................................................. ................................................... ................................................... .......................... 3
4.1 General .................................................. ................................................... ................................................... ................................................... 3
4.2 Selection of animal species .................................................. ................................................... ................................................... ... 3
4.3 Animal status .................................................. ................................................... ................................................... .................................... 3
4.4 Animal care and husbandry .................................................. ................................................... ................................................... . 3
4.5 Size and number of groups .................................................. ................................................... ................................................... ... 4
4.5.1 Size of groups .................................................. ................................................... ................................................... .............. 4
4.5.2 Number of groups .................................................. ................................................... ................................................... ... 4
4.5.3 Treatment controls .................................................. ................................................... ................................................... 4
4.6 Route of exposure .................................................. ................................................... ................................................... ......................... 5
4.7 Sample preparation ................................................... ................................................... ................................................... ................... 5
4.8 Dosing .................................................. ................................................... ................................................... ................................................... .. 5
4.8.1 Test sample administration .................................................. ................................................... ............................... 5
4.8.2 Dosage volumes .................................................. ................................................... ................................................... ........ 5
4.8.3 Dosage frequency .................................................. ................................................... ................................................... .... 6
4.9 Body weight and food/water consumption .................................................. ................................................... .............. 6
4.10 Clinical observations .................................................. ................................................... ................................................... .................. 6
4.11 Clinical pathology .................................................. ................................................... ................................................... ......................... 6
4.12 Anatomic pathology .................................................. ................................................... ................................................... .................... 7
4.13 Study designs .................................................. ................................................... ................................................... .................................... 7
4.14 Quality o f investigation .................................................. ................................................... ................................................... ............ 7
5 Acute systemic toxicity .................................................. ................................................... ................................................... ........................... 7
5.1 General .................................................. ................................................... ................................................... ................................................... 7
5.2 Study design .................................................. ................................................... ................................................... ...................................... 8
5.2.1 Preparations .................................................. ................................................... ................................................... ................ 8
5.2.2 Experimental animals ................................................... ................................................... ............................................ 8
5.2.3 Test conditions ................................................... ................................................... ................................................... .......... 8
5.2.4 Body weights .................................................. ................................................... ................................................... ............... 9
5.2.5 Clinical observations .................................................. ................................................... ............................................... 9
5.2.6 Pathology .................................................. ................................................... ................................................... ........................ 9
5.3 Evaluation criteria .................................................. ................................................... ................................................... ..................... 10
5.3.1 General ................................................... ................................................... ................................................... .......................... 10
5.3.2 Evaluation of results .................................................. ................................................... ............................................. 10
5.4 Final report ................................................... ................................................... ................................................... .................................... 10
6 Repeated exposure systemic toxicity (subacute, subchronic and chronic
systemic toxicity) .................................................. ................................................... ................................................... ...................................... 1 2
6.1 General .................................................. ................................................... ................................................... ................................................ 12
6.2 Study design .................................................. ................................................... ................................................... ................................... 12
6.2.1 Preparations .................................................. ................................................... ................................................... ............. 12
6.2.2 Experimental animals ................................................... ................................................... ......................................... 12
6.2.3 Test conditions ................................................... ................................................... ................................................... ....... 13
6.2.4 Body weights .................................................. ................................................... ................................................... ............ 13
6.2.5 Clinical observations .................................................. ................................................... ............................................ 13
6.2.6 Pathology .................................................. ................................................... ................................................... ..................... 13
6.3 Evaluation criteria .................................................. ................................................... ................................................... ..................... 14
6.3.1 General ................................................... ................................................... ................................................... .......................... 14
6.3.2 Evaluation of results .................................................. ................................................... ............................................. 14
© ISO 2017 – All rights reserved iii
ISO 10993-11:2017(E)
6.4 Final report ................................................... ................................................... ................................................... .................................... 15

Annex A (informative) Routes of administration ................................................... ................................................... ........................... 16
Annex B (informative) Dosage volumes .................................................. ................................................... ................................................... . 18
Annex C (informative) Common clinical signs and observations ................................................... ..................................... 19
Annex D (informative) Suggested haematology, clinical chemistry and urinalysis measurements 20
Annex E (informative) Suggested organ list for histopathological evaluation .................................................. ..... 22
Annex F (informative) Organ list for limited histopathology for medical devices subjected
to systemic toxicity testing .................................................. ................................................... ................................................... .............. 24
Annex G (informative) Information on material-mediated pyrogens .................................................. ........................... 25
Annex H (informative) Subchronic rat — Dual routes of parenteral administration ..................................... 26
Bibliography .................................................. ................................................... ................................................... ................................................... .................. 28
iv © ISO 2017 – All rights reserved

ISO 10993-11:2017(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work o f 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 o f
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 di fferent approval criteria needed for the
di fferent types o f ISO documents should be noted. This document was dra fted in accordance with the
editorial rules o f the ISO/IEC Directives, Part 2 (see www.iso. org/directives ).
Attention is drawn to the possibility that some o f the elements o f this document may be the subject o f
patent rights. ISO shall not be held responsible for identi fying any or all such patent rights. Details o f
any patent rights identified during the development o f 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 in formation given for the convenience o f users and does not
constitute an endorsement.
For an explanation on the voluntary nature o f standards, the meaning o f ISO specific terms and
expressions related to con formity assessment, as well as in formation about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following
URL: www.iso. org/iso/ foreword.html .
This document was prepared by Technical Committee ISO/TC 194 Biological and clinical evaluation of
.
medical devices
This third edition cancels and replaces the second edition (ISO 10993-11:2006), which has been
technically revised with the following changes:
a) reduction in group size for chronic toxicity testing in Table 1;
b) a new Annex F was added;
c) the original Annex F was moved to Annex G;
d) a new Annex H was added;
e) the Bibliography was updated.
A list of all parts in the ISO 10993 series can be found on the ISO website.
© ISO 2017 – All rights reserved v

ISO 1 099 3 -1 1 : 2 01 7(E)
Introduction
Sys tem ic toxic ity i s a p o tentia l advers e e ffe c t o f the u s e o f me d ic a l device s . G enera l i z e d e ffe c ts , as wel l
as organ and organ s ys tem e ffe c ts c an re s u lt from ab s orp tion, d i s tribution a nd me tab ol i s m o f le achate s
from the device or its materi a l s to p ar ts o f the b o dy with wh ich they are no t i n d i re c t contac t. T h i s
do c u ment add re s s e s the eva luation o f genera l i z e d s ys tem ic toxicity, no t s p e c i fic targe t orga n or organ
s ys tem toxic ity, even though the s e e ffe c ts may re s u lt from the s ys tem ic ab s or p tion and d i s tribution o f
toxicants.
Because of the broad range of medical devices, and their materials and intended uses, this document
i s no t overly pre s c rip tive . Wh i le it add re s s e s s p e c i fic me tho dolo gic a l as p e c ts to b e con s idere d i n the
de s ign o f s ys tem ic toxic ity te s ts , prop er s tudy de s ign h as to b e un iquely tai lore d to the natu re o f the
device’s materials and its intended clinical application.

Other elements of this document are prescriptive in nature, including those aspects that address
compl i ance with go o d lab orator y prac tice s and elements for i nclu s ion i n rep or ti ng.
Wh i le s ome s ys tem ic toxic ity te s ts (e . g. long term i mplantation or derma l toxic ity s tud ie s) c an be
de s igne d to s tudy s ys tem ic e ffe c ts a s wel l as lo c a l, c arc i no gen ic or repro duc tive e ffe c ts , th i s do c u ment
fo c u s e s on ly on tho s e a s p e c ts o f s uch s tud ie s , wh ich are i ntende d to add re s s s ys tem ic e ffe c ts . Stud ie s
which are intended to address other toxicological end points are addressed in ISO 10993-3, ISO 10993-6,
I S O 10 9 9 3 -10 and I S O/ T S 10 9 9 3 -2 0 .
P rior to conduc ti ng a s ys tem ic toxicity s tudy, a l l re as onably ava i l able data and s cienti fic a l ly s ound
me tho d s i n the plan n i ng and refi nement o f the s ys tem ic toxicity s tudy de s ign shou ld b e reviewe d .
T h i s i nclude s the s u itabi l ity o f u s e o f i nput data s uch a s e xi s ti ng toxicolo gica l data, data from chem ic a l
charac teri z ation s tud ie s and/or o ther biolo gic a l te s ts (i nclud i ng in vitro tests and less invasive in vivo
te s ts) for the refi nement o f s tudy de s ign, do s e s ele c tion, and/or s ele c tion o f p atholo gic a l end p oi nts to
cover i n the eva luation o f a s tudy. For the rep e ate d exp o s u re s ys tem ic toxic ity s tudy i n p ar tic u la r, the
us e o f s c ienti fic a l ly s ou nd s tudy de s ign, the u s e o f pi lo t s tud ie s and s tati s tica l s tudy de s ign a nd the
us e o f u nbi as e d, quantitative end p oi nts/me tho d s i n the p atholo gic a l (i nclud i ng h i s top atholo gic a l) and
cl i n ic a l chem i s tr y me tho d s are i mp or ta nt s o a s to ob ta i n data wh ich h ave s u fficient s cienti fic va l id ity.
Fi na l ly, toxicolo g y i s an i mp er fe c t s c ience . T he outcome o f any s i ngle te s t s hou ld no t b e the s ole b a s i s
for making a determination of whether a device is safe for its intended use.
vi © ISO 2017 – All rights reserved

INTERNATIONAL STANDARD ISO 10993-11:2017(E)
Biological evaluation of medical devices —

Part 11:
Tests for systemic toxicity
1 Scope
This do c u ment s p e c i fie s re qu i rements and give s gu idance on pro ce du re s to be fol lowe d in the
eva luation o f the p o tenti a l for me d ic a l device materi a l s to c au s e advers e s ys tem ic re ac tion s .
2 Normative references
T he fol lowi ng do c u ments are re ferre d to i n the tex t i n s uch a way th at s ome or a l l o f thei r content
con s titute s re qu i rements o f th i s do c u ment. For date d re ference s , on ly the e d ition cite d appl ie s . For
u ndate d re ference s , the late s t e d ition o f the re ference d do c ument (i nclud i ng a ny amend ments) appl ie s .
ISO 10993-1,Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk
management process
ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
3 Terms and definitions
ISO 10993-1
For the purp oses o f this do cument, the terms and definitions given in f and the ol lowing apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http: //w w w. ele c trop e d i a . org/
— ISO Online browsing platform: available at http: //w w w. i s o . org/obp
3.1
dose
dosage
amount o f tes t s ample adminis tered (e. g. mas s , volume) expres sed p er unit o f b o dy weight or s ur face area
3.2
dose-effect
relation sh ip b e twe en the do s age and the magn itude o f a defi ne d biolo gic a l e ffe c t either i n an i nd ividua l
or in a population sample
3.3
dose-response
relationship of dosage to the spectrum of effects related to the exposure
N o te 1 to entr y: T here a re two typ e s o f do s e - re s p o n s e rel atio n s h ip s . T he fi rs t typ e is the re s p o n s e of an
i nd i vidu a l to a ra n ge o f do s e s . T he s e cond typ e i s the d i s tr ib utio n o f re s p on s e s o f a p op u l atio n o f i nd i vidu a l s to
a range of doses.
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ISO 1 099 3 -1 1 : 2 01 7(E)
3 .4
leachable substance
chem ic a l remove d from a device or materi a l by the ac tion o f water or o ther l iqu id s relate d to the u s e o f
the device
N o te 1 to entr y: E xa mp le s o f le ach ab le s ub s ta nce s a re add iti ve s , s ter i l a nt re s idue s , p ro ce s s re s idue s , de gradation
pro duc ts , s ol vents , p l a s tic i z ers , lub ric a nts , c ata l ys ts , s tab i l i z ers , a nti- oxid a nts , co lo u r i ng agents , fi l lers a nd
monomers.
3.5
limit tes t
use of a single group treated at a suitable dosage of test sample in order to delineate the presence or
absence of a toxic hazard
3 .6
s ystemic toxicity
toxicity that i s no t l i m ite d to advers e e ffe c ts at the s ite o f contac t b e twe en the b o dy a nd the device
N o te 1 to entr y: S ys tem ic toxic i ty re qu i re s ab s or p tio n a nd d i s tr ibution o f a toxic a nt fro m i ts entr y p oi nt to a
distant site at which deleterious effects are produced.

3 .7
acute s ystemic toxicity
advers e e ffe c ts o cc u rri ng at any ti me with i n 7 2 h a fter s i ngle, mu ltiple or conti nuou s exp o s u re s o f a
test sample for 24 h

3.8
subacute s ystemic toxicity
adverse effects occurring after multiple or continuous exposure between 24 h and 28 d
N o te 1 to entr y: S i nce th i s ter m i s s em a ntic a l l y i ncor re c t, the advers e e ffe c ts o cc u r r i n g with i n the s p e c i fie d ti me
p er io d m ay a l s o b e de s c r ib e d a s a s ho r t- ter m rep e ate d e xp o s u re s ys tem ic toxic i ty s tudy. T he s ele c tio n o f ti me
i nter va l s b e twe en 14 d a nd 2 8 d i s con s i s tent with mo s t i nter n ation a l re gu l ator y gu idel i ne s a nd co n s idere d
a re a s on ab le ap pro ach . Sub ac ute i ntraveno u s s tud ie s a re genera l l y de fi ne d as tre atment du ration s o f >2 4 h
but <14 d.
3 .9
subchronic s ystemic toxicity
adverse effects occurring after the repeated or continuous administration of a test sample for a part of
the lifespan
N o te 1 to entr y: Sub ch ro n ic toxic ity s tud ie s a re u s u a l l y 9 0 d i n ro dents b ut no t e xce e d i n g 10 % o f the l i fe s p a n
o f o ther s p e c ie s . Sub ch ro n ic i ntraveno u s s tud ie s a re genera l l y de fi ne d a s tre atment du ratio n s o f 14 d to 2 8 d fo r

ro dents a nd non-ro dents , re s p e c ti vel y.
3 .10
chronic s ys temic toxicity
advers e e ffe c ts o cc u rri ng a fter the rep e ate d or conti nuou s ad m i n i s tration o f a te s t s ample for a maj or
part of the life span

N o te 1 to entr y: C h ron ic toxic ity s tud ie s u s u a l l y h ave a du ratio n o f 6 month s to 1 2 month s .
3 .11
tes t sample
materia l , device, device p or tion, comp onent, e x trac t or p or tion there o f th at i s s ubj e c te d to biolo gic a l or
chemical testing or evaluation
2 © ISO 2017 – All rights reserved

ISO 1 0993 -1 1 : 2 0 1 7(E)
4 General considerations
4.1 General
Be fore a decision to per form a systemic toxicity test is made, ISO 10993-1 shall be taken into account.
The decision to per form a test shall be justified on the basis o f an assessment o f the risk o f systemic
toxicity. Selection o f the appropriate test(s) for a device shall be in accordance with ISO 10993-1, giving
due consideration to mode and duration of contact.
Testing shall be per formed on the final product and/or representative component samples o f the final
product and/or materials. Test samples shall reflect the conditions under which the device is normally
manu factured and processed. I f deviations are necessary, they shall be recorded in the test report,
together with their justification. For hazard identification purposes, it may be necessary to exaggerate
exposure to the test samples.
Physical and chemical properties o f the test sample including, for example, pH, stability, viscosity,
osmolality, bu ffering capacity, solubility and sterility, are some factors to consider when designing
the study.
When animal tests are considered, all reasonably and practically available replacement, reduction and
refinement alternatives should be identified and implemented to satis fy the provisions o f ISO 10993-2.
For in vivo acute toxicity testing, in vitro cytotoxicity data are use ful in estimating starting doses.
4.2 Selection of animal species
There is no absolute criterion for selecting a particular animal species for systemic toxicity testing o f
medical devices. However, the species used shall be scientifically justified and in line with the provisions
of ISO 10993-2. For acute oral, intravenous, dermal and inhalation studies of medical devices the
rodent (mouse or rat) is preferred with the option of the rabbit (lagomorph) in the case of dermal and
implantation studies. Other non-rodent species may also need to be considered for testing, recognizing
that a number o f factors might dictate the number or choice o f species for study.
It is pre ferred that a single animal species and strain are used when a series o f systemic toxicity studies
o f di fferent durations are per formed, e.g. acute, subacute, subchronic and/or chronic systemic toxicity.
This controls the variability between species and strains and facilitates an evaluation related solely
to study duration. Should multiple species or strains be used, justification for their selection shall be
documented.
4.3 Animal status
Generally, healthy purpose-bred young adult animals o f known origin and with defined microbiological
health status should be used. At the commencement o f the study, the weight variation o f animals used
within a sex should not exceed ±20 % o f the mean weight. When females are used, they should be
nulliparous and non-pregnant. Animal selection shall be justified.
4.4 Animal care and husbandry
Care and handling o f animals shall con form to accepted animal husbandry guidelines. Animals shall
be acclimatized to the laboratory conditions prior to treatment and the period o f time documented.
Control o f environmental conditions and proper animal care techniques are necessary for meaning ful
results. Dietary constituents and bedding materials that are known to produce or influence toxicity
should be properly characterized and their potential to influence test results taken into account.

ISO 1 099 3 -1 1 : 2 01 7(E)
4.5 Size and number of groups
4.5 .1 Size of groups
T he pre c i s ion o f the s ys tem ic toxic ity te s t i s dep endent to a la rge e x tent on the nu mb er o f a n i ma l s
used per dose level. The degree of precision needed and, in turn, the number of animals per dose group
ne e de d dep end s on the pu rp o s e o f the s tudy.
Group s i z e s shou ld lo gic a l ly i nc re a s e with the du ration o f tre atment, s uch that at the end o f the s tudy
enough a n i ma l s i n ever y group are ava i lable for thorough biolo gic a l eva luation . H owever, the m i n i mu m
number of animals should be used consistent with obtaining meaningful results (see ISO 10993-2).
Recommended minimum group sizes, all routes considered, are given in Table 1.
Table 1 — Recommended minimum group sizes
Study type Rodent Non-ro dent
Acute a 5 3
Subacute 10 (5 per sex) a 6 (3 per sex) a
Subchronic 20 (10 per sex) a 8 (4 per sex) a
Chronic 30 (15 per sex) b, c c
a Testing in a single sex is acceptable. When a device is
f
i n te n de d or use i n o n l y o ne s ex, te s ti n g s h o u l d be do ne in
that sex.
b The recommendation for rodents refers to one dose-level
group testing. Where additional exaggerated dose groups are
i nclude d the re co m mende d g ro up s i z e m ay b e re duce d to 1 0
per sex.
c FREE standards from Standard
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s tati s tic a l co n s u ltatio n or ch ro n ic s tudy no n-
rodent group size is recommended. The number of animals

tested should be based on the minimum required to provide
meaningful data. Enough animals shall remain at the
f
ter m i n atio n o the s tudy to en s u re p ro p er s tati s tic a l e va lu atio n
of the results.
4.5 .2 Number of groups
One dose group treated at a suitable dosage of test sample in a single species could delineate the
presence or absence of a toxic hazard (i.e. limit test). However, other multi-dose or dose response
studies require multiple groups to delineate the toxic response.
T he nu mb er o f tre atment group s may b e i ncre as e d when attemp ti ng to ch arac teri z e a do s e re s p on s e
using exaggerated doses. The following examples for exaggerating the dose should be considered:
— multiples of the clinical surface area of exposure;
— multiples of the duration of exposure;
— multiples of the extractable fraction or the individual chemicals;
— multiple administrations within a 24-h period.
O ther me tho d s to e xaggerate the do s e may b e accep table . T he me tho d u s e d s ha l l b e j u s ti fie d .
4.5 .3 Treatment controls
D ep end i ng on the obj e c tive o f the s tudy, the natu re o f the te s t a r ticle and the route o f exp o s u re, ne gati ve,
veh icle and/or sh am-tre ate d control s shou ld b e i ncorp orate d i nto a l l s ys tem ic toxicity s tud ie s . T he s e
controls shall mimic the test sample preparation and treatment procedure.

ISO 1 0993 -1 1 : 2 0 1 7(E)
4.6 Route of exposure
Medical devices or their leachable substances may gain access to the body by multiple routes o f
exposure. The test route o f exposure shall be the most clinically relevant to the use o f the device, where
possible. I f an alternative route o f exposure is necessary, it shall be justified. Examples o f routes o f
administration can be found in Annex A.
4.7 Sample preparation
Guidance on sample preparation and stability is given in ISO 10993-12.
4.8 Dosing
4.8.1 Test sample administration
Procedures should be designed to avoid physiological changes or animal wel fare problems not directly
related to the toxicity o f the test material. I f a single daily dose o f a su fficient volume or concentration is
not possible, the dose may be given in smaller fractions over a period not exceeding 24 h.
Test samples shall be delivered at a physiologically acceptable temperature. In general, room or body
temperature is a common practice. Deviations shall be justified.
Vehicles administered by a parenteral route should be physiologically compatible. When necessary,
sample filtration to remove particulates should be used and documented. When medical devices and/or
test samples in the form o f nanomaterials are to be evaluated sample filtrations shall not be per formed.
(see ISO/TR 10993-22).
Restraint o f animals in repeated exposure systemic toxicity studies should generally be limited to
between 4 h and 6 h per day. The nature and the duration o f restraint should be the minimum required
to meet the scientific objectives and should not o f themselves compromise the wel fare o f the test
animals. Deviations shall be justified.
When restraint is required animals should be acclimatized to the restraint device prior to test sample
administration.
4.8.2 Dosage volumes
Guidance on dosage volume is summarized in Annex B. When multiple dosage groups are used,
variability in the test volume may be minimized by adjusting the concentration to ensure a constant
volume at all doses. Use of dosage volumes greater than those given in Annex B shall be justified.
Large dose volumes administered by the oral route should be avoided because they have been shown
to overload the stomach capacity and pass immediately into the small bowel. Large volumes may also
reflux into the oesophagus.
Intramuscular administration is also volume-limited, depending on size of the animal and the muscular
site. Species-specific intramuscular administration volumes are addressed in Annex B.
Bolus intravenous injection volumes are usually given over a period o f approximately 1 min. The rate o f
injection is an important factor and it is suggested that, for rodents, the rate shall not exceed 2 ml/min.
Slow or timed injection, or intravenous in fusion, may be required for large volume administration.
Regardless o f the calculated rate, the rate o f fluid administration shall be stopped or decreased i f the
animal demonstrates a marked change in clinical condition.
Slow intravenous injection rates may be necessary for test samples limited by solubility or irritancy.
Continuous in fusion may be used i f clinically indicated. The volume and rate o f administration will
depend on the substance being given and take into account standard fluid therapy practice. As a guide,

ISO 10993-11:2017(E)
the volume administered on a single occasion will be <10 % o f the circulating blood volume over 2 h.
Minimal e ffective restraint o f test animals is a key factor to be considered for prolonged in fusion.
For subcutaneous administration of test article, refer to Annex B. The rate and extent of absorption
depends on the test sample formulation.
4.8.3 Dosage frequency
The dosage frequency should be based on clinical relevancy. Exaggerated procedures shall be clearly
specified and justified.
In acute systemic toxicity studies, the animals should be exposed to the test sample in a single dose or
with multiple fractions of the dose given within a 24 h period.
In repeated exposure studies the animals should be dosed with the test sample daily, seven days each
week for the duration o f the test. Other dosage regimens may be acceptable but shall be justified.
4.9 Body weight and food/water consumption

Body weight change and changes in food and water consumption may be attributed to the e ffects o f a
test article. Consequently, individual weights o f the animals shall be determined shortly be fore the test
sample is administered (e.g. usually within 24 h for single or acute dosing, and no more than 7 d for
repeated exposure studies), at regular intervals throughout the study and at study termination. When
dosing by body weight, the most recent body weight should be utilized.
Measurements of food and water consumption, as appropriate, shall be considered for longer-term
repeated exposure studies.
4.10 Clinical observations
Clinical observations should be per formed by trained individuals to ensure consistent reporting. The
frequency and duration o f observation should be determined by the nature and severity o f the toxic
reactions, rate o f onset and recovery period. Increased frequency o f observation may be necessary in the
early phase o f a study, especially acute studies. The time at which signs o f toxicity appear and disappear,
their duration and the time o f death are important, especially i f there is a tendency for adverse clinical
signs or deaths to be delayed. Humane end points, as defined by national or international animal wel fare
guidelines, should be used in order to avoid unnecessary su ffering. General clinical observations shall
consider the peak period of anticipated effects after dosing.
Observations shall be recorded systematically as they are made. Records shall be maintained for
each animal.
Cage-side observations for viability or overt clinical signs shall be recorded at least once each day using
common laboratory descriptors o f clinical e ffects (see Annex C).
Morbidity and mortality observations shall be recorded at least twice daily for long-term repeated
exposure studies. A more extensive screening for adverse clinical signs may be considered on at least a
weekly basis for longer-term repeated exposure studies.
4.11 Clinical pathology

Haematology and clinical chemistry analyses are per formed to investigate toxic e ffects in tissues,
organs and other systems. When indicated, these analyses shall be per formed on blood samples
obtained from repeated exposure study animals at least just prior to, or as a part o f, the procedure for
scheduled animal termination. Fasting o f animals prior to blood sampling may be necessary in some
cases. When scientifically indicated, urinalysis can be per formed during the last week o f a long-term
repeated exposure study using timed (e.g. 16 h to 24 h) urine volume collection.

ISO 1 0993 -1 1 : 2 0 1 7(E)
Suggested haematology, clinical chemistry and urinalysis parameters for evaluation are listed in
Annex D.
4.1 2 Anatomic pathology
When clinically indicated, gross pathological evaluations should be considered for acute systemic
toxicity studies.
All animals in repeated exposure studies shall be subjected to a full, detailed gross necropsy which
includes care ful examination o f the external sur face o f the body, all orifices, and the cranial, thoracic,
and abdominal cavities and their contents. Selected organs for weighing should be trimmed o f any
adherent tissue, as appropriate, and their wet weight taken as soon as possible to avoid drying.
Annex E suggests the tissues that should be weighed and preserved in an appropriate fixation medium
for histopathological examination.
A summary o f minimum observations for each type o f study is given in Table 2.
Table 2 — Summary of observations
Ob ser vation Acute Sub acute/s ub chronic C hronic a

Body weight change + + +
Clinical observations + + +
Clinical pathology b a, b +
Gross pathology b + +
Organ weights b + +
Histopathology b a, b +
+ Data should be provided.
a Chronic systemic toxicity testing is generally a time extension o f subacute/subchronic testing, justified
by the human exposure period. Many o f the same parameters are recorded and reported. Group sizes may
be increased to include satellite groups for which some, or all, o f these observations may be made.
b Consideration should be given to these measurements when clinically indicated or i f longer exposure
testing is not anticipated. Lists o f suggested bodily fluids and organ/tissue analyses are included in
Annex D, Annex E and Annex F.
4.1 3 Study designs
Study designs are listed in subsequent clauses o f this document. Expert consultation for study design is
recommended.
4.1 4 Quality of investigation
Good laboratory practices deal with the organization, process and conditions under which laboratory
studies are planned, performed, monitored, recorded and reported. These practices are intended to
promote the quality and validity o f the test data. They also support the global harmonization e ffort by
facilitating the memoranda o f understanding between trading nations. Systemic toxicity studies shall
be conducted following such principles.
5 Acute systemic toxicity
5 .1 General
Acute systemic toxicity provides general in formation on health hazards likely to arise from an acute
exposure by the intended clinical route. An acute toxicity study might be an initial step in establishing
a dosage regimen in subacute/subchronic and other studies and may provide in formation on the
mode o f toxic action o f a substance by the intended clinical exposure route. Subsequent to test sample

ISO 1 099 3 -1 1 : 2 01 7(E)
administration in acute systemic toxicity testing, observations are made o f e ffects (e.g. adverse clinical
signs, body weight change, gross pathological findings) and deaths. Animals showing severe and
enduring signs o f distress and pain need to be euthanized immediately. Corrosive or irritating materials
known to cause marked pain or distress should be reported as such and need not be tested.
The Interagency Coordinating Committee on the Validation o f Alternative Methods (ICCVAM) and
the European Centre for the Validation of Alternative Methods (ECVAM) have validated the in vitro
cytotoxicity test as an alternative to acute oral toxicity testing. Humane end points, as defined by
national or international animal wel fare guidelines, should be used in order to avoid unnecessary
suffering.
5 .2 Study design
5 .2 .1 Preparations
Healthy young adult animals are acclimatized to the laboratory conditions for at least 5 d prior to the test.
Shorter durations shall be justified. Animals are then randomized and assigned to the treatment groups.
5 .2 .2 Experimental animals
5 .2 .2 .1 Selection of species
Typically, a rodent species (rat, mouse) will be used. Characteristics o f the model (age, weight, etc.) are
as specified in 4.2 and 4.3 . I f non-rodent species are used their use shall be scientifically justified.
5 .2 .2 .2 Number and sex
The number and type

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5 .2 .2 .3 Housing and feeding conditions
The temperature and the relative humidity in the experimental animal rooms should be appropriate
for the species, e.g. (22 ± 3) °C and 30 % to 70 % RH, for mice. Typically, the artificial lighting sequence
should be 12 h light, 12 h dark.
For feeding, standardized commercial laboratory diets may be used with an unlimited supply o f
drinking water. Animals should be caged in-groups by sex or individually, as appropriate; for group
housing not more than five animals shall be housed per cage.
5 .2 .3 Test conditions
5 .2 .3 .1 Dose levels
Dose levels shall be as specified in 4.8.

Animals in the control group should be handled in an identical manner to the test group subjects with
the exception of not being dosed with the test sample.
5 .2 .3 .2 Procedure
The animals receive a single dose o f the test sample or, when necessary, multiple doses within a single
24 h period. Signs o f toxicity should be recorded as they are observed including the time o f onset,
degree and duration.
Regular observation o f the animals is necessary to ensure that animals are not lost from the study due
to cannibalism, autolysis o f tissues or misplacement. At the end o f the study, all surviving animals are
euthanized. Any moribund animals should be removed and euthanized when noticed to exhibit such

ISO 10993-11:2017(E)
behaviour. Methods used for euthanasia should be in accordance with national or international animal
welfare guidelines.
The observation schedules and humane end points applied should preclude the possibility o f animals
being found dead as a direct consequence o f test sample toxicity.
5.2.4 Body weights

Body weight measurements should be made immediately be fore dosing, daily for the first three days
a fter dosing, weekly a fter the first dose i f indicated by study duration, and at the end o f the study.
5.2.5 Clinical observations

The observation period for an acute systemic toxicity study shall be at least 3 d, or longer when
deemed appropriate. Specifics o f frequency and observation type are specified in 4.10 and Annex C.
In all cases, observations shall be made at a frequency, and appropriate actions taken, to minimize the
loss o f animals to the study, e.g. necropsy or re frigeration o f those animals found dead and isolation or
sacrifice o f weak or moribund animals. Cage-side observations should include, but not be limited to,
changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and
central nervous system, somatomotor activity and behaviour pattern, using the descriptors provided in
Annex C.
5.2.6 Pathology
5.2.6.1 Clinical pathology

Clinical pathology evaluations shall be considered when there is an indication, such as for device
materials with expected or observed toxicity (from a prior study), or for new device materials where
there is no previous experience. When clinical pathology evaluations are per formed, the following
examinations shall be considered.
a) Haematology, as specified in Annex D, should be considered for investigation at the end of the
test period.
b) Clinical biochemical determination on blood, as listed in Annex D, should be considered at the end
of the test period. Test areas which are considered appropriate to acute exposure studies are liver
and kidney function. Additional clinical biochemistry may be utilized where necessary to extend
the observation of the observed effects.
Urinalysis (see Annex D) is not necessary on a routine basis but only when there is an indication based
on expected or observed toxicity. Suggested parameters are listed in Annex D.
5.2.6.2 Gross pathology

Gross pathological evaluations shall be considered when there is an indication, such as for device
materials with expected or observed toxicity (from a prior study), or for new device materials where
there is no previous experience. This should include an examination o f the external sur face o f the body,
all orifices, and the cranial, thoracic and abdominal cavities and their contents. When appropriate,
consideration should also be given to recording the weight o f the brain, liver, kidneys, adrenals and
testes, which should be weighed wet as soon as possible a fter dissection to avoid drying and subsequent
falsely low values.
5.2.6.3 Histopathology
Full histopathology is not typically carried out on organs and tissues from animals in the acute systemic
toxicity study, unless indicated specifically by unique gross necropsy findings.

ISO 1 099 3 -1 1 : 2 01 7(E)
5 .3 Evaluation criteria
5 .3 .1 General
Depending on the test design utilized, the following evaluation criteria apply.
a) For pharmacopoeia-type testing.
1) I f during the observation period o f an acute systemic toxicity test none o f the animals treated
with the test sample shows a significantly greater biological reactivity than animals treated
with the vehicle control, the sample meets the requirements of this test.
2) Using five animals, i f two or more animals die, or i f behaviour such as convulsions or
prostration occurs in two or more animals, or i f a final (end o f study) body weight loss greater
than 10 % occurs in three or more animals, the sample does not meet the requirements o f the
test. Any transitory body weight loss should be critically evaluated along with other clinical
observations in the assessment o f systemic toxicity.
3) I f any animals treated with the sample show only slight signs o f biological reactivity, and not
more than one animal shows gross symptoms o f biological reactivity or dies, repeat the testing
using groups of 10 animals.
4) On the repeat test, i f all 10 animals treated with the sample show no scientifically meaning ful
biological reactivity above the vehicle control animals during the observation period, the
sample meets the requirements of this test.
b) For non-pharmacopoeia acute systemic toxicity tests.
The option exists to perform evaluations using more extensive methods including clinical and
anatomic pathology, which
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5 .3 .2 Evaluation of results
The findings o f an acute systemic toxicity study should be evaluated in conjunction with the findings
o f preceding studies, i f available, and considered in terms o f the toxic e ffects and the gross necropsy
findings, i f observed. The evaluation shall include the relationship between the dose o f the test
substance and the presence or absence and the incidence and severity o f abnormalities, including
behavioural and clinical abnormalities, gross lesions, body weight changes, e ffects on mortality and
any other general or specific e ffects.
5 .4 Final report
The following in formation, where applicable, shall be contained in the final test report for the acute
systemic toxicity study.
a) Details o f the testing laboratory and study sponsor, and rationale for selection o f the study design.
b) Test sample:
1) physical nature, purity and physiochemical properties, as appropriate;

ISO 1 0993 -1 1 : 2 01 7(E)
2) o ther identi fic ation data .
c) Extraction solvent or vehicle (if appropriate):

1) j u s ti fic ation for choice o f ex trac tion s olvent or veh icle i f o ther tha n tho s e l i s te d i n I S O 10 9 9 3 -1 2 .
d) Test animals:
1) s p e cie s/s trai n u s e d;
2) number, age and sex of animals;

3) source including microbiological status (e.g. barrier raised, conventional), housing conditions
(temp eratu re, hu m id ity, b e dd i ng , l ighti ng , d ie t, e tc .) ;
4) weights at s tudy i niti ation .
e) Test conditions:
1) rationale for dose selection;
2) de ta i l s of te s t s a mple formu lation/prep aration; ach ieve d concentration s; s tabi l ity a nd
homo geneity, i f appropriate;
3) details of the administration of the test sample;

4) convers ion from te s t s ample concentration ( ppm) to the ac tua l do s e (mg/ kg B W ) , i f appl ic able;
5) de ta i l s o f fo o d, water and b e dd i ng qua l ity.
f) Results:
1) data may b e s u m ma ri z e d i n tabu lar form, s howi ng for e ach control and te s t group the nu mb er
of animals at the start of the test, the number of animals showing adverse clinical signs, and
the nu mb er o f an i ma l s d i s playi ng b o dy weight cha nge s;
2) b o dy weight/ b o dy weight change;
3) food and water consumption, if applicable;

4) toxic re s p on s e data by s ex a nd do s e level, i nclud i ng s ign s o f toxicity;
5) natu re, s everity and du ration o f cl i n ic a l ob s er vation s (whe ther revers ible or no t) ;
6) neurobehavioural assessments, if applicable;

7) haematological tests utilized and results with relevant control data, if applicable;
8) cl i n ic a l bio chem i s tr y te s ts uti l i z e d and re s u lts with relevant control data, i f appl icable;
9) u ri na lys i s te s ts uti l i z e d and re s u lts with relevant control data, i f appl ic able;
10) term i na l b o dy weight and orga n weight data, i f appl ic able;
11) ne crop s y fi nd i ngs;
12) de ta i le d de s crip tion o f a l l h i s top atholo gic a l fi nd i ngs , i f appl ic able;
13) s tati s tic a l eva luation o f re s u lts , i f u s e d , a nd a d i s c u s s ion o f thei r biolo gic a l s ign i fic ance .
g) Discussion of results.
h) Conclusions.
i) Qua l ity as s u ra nce s tatement.

ISO 1 099 3 -1 1 : 2 01 7(E)
An acute systemic toxicity study will provide in formation on the e ffects o f acute exposure to a test
substance. Extrapolation o f the results o f the study to humans is valid to a limited degree but it can
provide useful information on permissible exposure.
6 Repeated exposure systemic toxicity (subacute, subchronic and chronic
systemic toxicity)
6.1 General
While acute toxicity deals with the adverse e ffects o f single doses (or limited exposure), a more common
form o f human exposure to many medical devices is in the form o f repeated or continuous exposures.
E ffects from repeated or continuous exposure may potentially occur due to accumulation o f chemicals
in tissues or by other mechanisms. Long term testing (subacute, subchronic, chronic) can identi fy these
potential effects.
Repeated exposure systemic toxicity tests provide in formation on health hazards likely to arise from
a prolonged exposure by the intended clinical route. It might also provide in formation on the mode o f
toxic action o f a substance by the intended clinical exposure route.
Repeated exposure systemic toxicity studies will provide detailed in formation on toxic e ffects, target
organs, reversibility or other e ffects and may serve as the basis for sa fety estimation. Results o f these
studies provide important in formation that is reflected in the extent o f the guidance o f clinical and
anatomic pathology investigations.
Repeated exposure studies do not generally provide a retest criterion. Rather, group sizes are designed
to accommodate a statistical assessment of the recorded observations (see Table 1).
Because of the variable durations
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6.2 Study design
6.2 .1 Preparations
Healthy young adult animals are acclimatized to the laboratory conditions for at least 5 d prior to the
test. Animals are then randomized and assigned to the treatment groups.
6.2 .2 Experimental animals
6.2 .2 .1 Selection of species
Typically the rodent (rat, mouse) will be used. Characteristics o f the model (age, weight, etc.) are
specified in 4.2 and 4.3 . When non-rodent species are used they shall be scientifically justified.
6.2 .2 .2 Number and sex
The number and type o f groups, animals per group, and sex are as specified in 4.5 . When scientifically
justified, consideration should be given to the use o f satellite animals treated with the high dose level
along with satellite controls for a predetermined period beyond the terminal euthanasia. This group,
with its controls, may be used to examine treatment e ffects including reversibility, persistence or delayed
toxic effects. For subchronic studies the satellite animals shall be maintained for not less than 28 d.
6.2 .2 .3 Housing and feeding conditions
The temperature and the relative humidity in the experimental animal rooms should be appropriate
for the species, e.g. (22 ± 3) °C and 30 % to 70 % RH, for rats. Typically, the artificial lighting sequence
should be 12 h light, 12 h dark.
ISO 10993-11:2017(E)
For feeding, standardized commercial laboratory diets may be used with an unlimited supply o f
drinking water. Animals may be caged in groups by sex or individually with justification, as appropriate;
for group housing not more than five animals should be housed per cage.
6.2.3 Test conditions
6.2.3.1 Dose levels

The dose to use for toxicity tests o f medical devices shall be defined in relation to the results o f risk
assessment, balancing the clinical exposure dose with the use o f sa fety factors, as applicable. Except
for treatment with the test substance, animals in the control group should be handled in an identical
manner to the test group subjects.
Unlike classical chemical studies o f repeated exposure systemic toxicity, repeated exposure studies
with medical devices often do not result in a dose-response effect, thus a toxic effect at the dose level
investigated is not mandatory.
6.2.3.2 Procedure
Animals should be dosed ideally 7 d/week for the duration o f the study. For longer term repeated
exposure studies, dosing on 5 d/week basis is acceptable but should be documented and justified.
6.2.4 Body weights

Body weight measurements should be made immediately be fore dosing, weekly a fter the first dose i f
indicated by study duration, and at the end o f the study.
6.2.5 Clinical observations

The observation period for a repeated dose systemic toxicity study shall be appropriate for the
duration o f the study. Specifics o f frequency and observation type are specified in 4.10 and Annex C.
In all cases, observations shall be made at a frequency, and appropriate actions taken, to minimize the
loss o f animals to the study, e.g. necropsy or re frigeration o f those animals found dead and isolation or
euthanasia of weak or moribund animals. Cage-side observations should include, but not be limited to,
changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and
central nervous system, somatomotor activity and behaviour pattern, using the descriptors provided in
Annex C.
Typically, ophthalmologic examinations, using an ophthalmoscope or equivalent suitable equipment,
should be made prior to the administration o f the test substance and at the termination o f the study,
pre ferably in all animals but at least in the high dose and control groups. I f changes in the eyes are
detected, all animals should be examined. Exception to examination should be documented and
justified.
6.2.6 Pathology
6.2.6.1 Clinical pathology

The following examinations should be made.
a) Haematology, as specified in Annex D, should be investigated at the end of the test period. Depending
on the length o f the study, more frequent sampling should be considered.
b) Clinical biochemical determination on blood should be carried out at the end of the test period.
Depending on the length o f the study, more frequent sampling should be considered. Test areas that
are considered appropriate to all repeated exposure studies are electrolyte balance, carbohydrate
metabolism, and liver and kidney function. The selection o f specific tests may be influenced by
observations on the mode of action of the test substance. Suggested determinations are listed
ISO 1 099 3 -1 1 : 2 01 7(E)
in Annex D . Additional clinical biochemistry may be utilized where necessary to extend the
observation of the observed effects.
Urinalysis (see Annex D) is not necessary on a routine basis but only when there is an indication based
on expected or observed toxicity.
Historical data for normal values are useful for establishing baseline levels and for comparison with
concurrent study controls. I f historical baseline data are deemed inadequate, consideration should be
given to the collection o f this in formation for animals o f the same age, sex, strain and source, pre ferably
within the same laboratory.
6.2 .6.2 Gross pathology
All animals should be subjected to full gross necropsy, which includes examination o f the external
sur face o f the body, all orifices, and the cranial, thoracic and abdominal cavities and their contents.
The adrenals, brain, epididymis, heart, kidneys, liver, ovaries, spleen, testes, thymus and uterus should
be weighed wet as soon as possible a fter dissection to avoid drying and subsequent falsely low values.
The organs and tissues listed in Annex E should be preserved in a suitable medium for possible future
histopathological examination.
6.2 .6.3 Histopathology
a) Full histopathology should be carried out on organs and tissues from animals in the control and
high dose groups.
b) All gross lesions should be examined.
c) The lungs o f animals in the low and intermediate dose groups, i f used, should be subjected to
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not be required routinely on the animals in these groups but shall always be carried out in organs
which showed evidence of lesions in the high dose group.
d) When a satellite group is used, histopathology may be per formed on tissues and organs identified
as showing effects in the treated groups.
e) In general, for chronic studies, sentinel animals should be used for monitoring the occurrence of
in fectious agents. Serology or histology o f sentinel groups may be per formed as indicated.
f ) During selection o f organs for histopathology, due consideration should be given to chemical
characterization o f device materials. For example, i f the device is coated with drugs/pharmaceutical
agents, then target organs for those chemicals should be studied in treated animals for any adverse
effects.
6.3 Evaluation criteria
6.3 .1 General
Data may be summarized in tabular form, showing, for each test group, the number o f animals at
the start o f the test, the number o f animals showing lesions, the types o f lesions and the percentage
o f animals displaying each type o f lesion. Statistical evaluations should be per formed but biological
relevance should be considered. Generally accepted statistical methods should be used and selected
during the design phase o f the study.
6.3 .2 Evaluation of results
The findings o f a repeated exposure study should be evaluated in conjunction with the findings o f
preceding studies and considered in terms o f the toxic e ffects and the necropsy and histopathological

ISO 1 0993 -1 1 : 2 0 1 7(E)
findings. The evaluation shall include the relationship between the dose o f the test substance and the
observed effects. Observed effects including behavioural and clinical abnormalities, gross lesions,
microscopic changes, e ffects on mortality and any other e ffects should be evaluated for their biological
significance. Evaluation o f observed e ffects should also consider their relevance to humans.
6.4 Final report
The information given in 5.4 shall be contained in the final report for the repeated exposure systemic
toxicity study. In addition, the following in formation shall be provided:
— haematological tests utilized and results with relevant control data;
— clinical biochemistry tests utilized and results with relevant control data;
— histopathological findings;
— a statistical evaluation o f results, where used, and a discussion o f their biological significance.
A long-term systemic toxicity study will provide in formation on the e ffects o f repeated exposure to a
test substance. Extrapolation o f the results o f the study to humans is valid to a limited degree but it can
provide useful information on permissible human exposure.

ISO 1 099 3 -1 1 : 2 01 7(E)
Annex A
(informative)
Routes of administration
A.1 General
Several routes of administration are listed in A.2 to A.10 . O ther route s o f ad m i n i s tration may b e more
cl i n ic a l ly relevant and shou ld b e uti l i z e d . T he mo s t relevant route o f ad m i n i s tration s ha l l b e u s e d . I f an
a lternative route o f ad m i n i s tration i s u s e d it s ha l l b e j u s ti fie d . E xp er t con s u ltation i s s ugge s te d when
designing appropriate studies.

A.2 Dermal
Te s ts for s ys tem ic toxic ity b y the derma l route may b e appropriate for s u r face device s . C on s ideration
should be given to limiting animal oral access to the test sample.

A.3 Implantation
Te s ts for s ys tem ic toxic ity b y i mplantation may b e appropri ate for i mpl ante d device s . T he te s t may
b e appropriate for d i re c t te s ti ng o f a materia l by appl ic ation to a genera l or s p e ci fic a re a . S hap e and
texture of the test Get

article should be taken into consideration. Methods for implantation can be found in
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A.4 Inhalation
Te s ts for s ys tem ic toxicity by the i n ha l ation route may b e appropri ate for device s with a contac t
envi ron ment conduc ive to volati le chem ic a l vap ou r le ach i ng or for an aero s ol/p a r tic u l ate te s t s ample
with p o tenti a l for i n ha lation . P ro to col s p e c i fics for th i s route o f ad m i n i s tration may b e fou nd i n mo s t
de d ic ate d tex ts for i n h a lation toxicolo g y.
A.5 Intradermal
Te s ts for s ys tem ic toxicity b y the i ntraderma l route may b e appropri ate for a device with a n i ntraderma l
contac t envi ron ment conduc ive to chem ic a l le ach i ng. Te s t s a mple s are typic a l ly ad m i n i s tere d d i re c tly
to the i ntraderma l region b y i nj e c tion . T he u s e o f mu ltiple tre atment s ite s s hou ld b e cle arly s p e ci fie d
and j u s ti fie d .
A.6 Intramuscular
Te s ts for s ys tem ic toxic ity b y the i ntramu s c u l ar route may b e appropri ate for device s with a mu s cle
ti s s ue contac t envi ron ment conducive to chem ic a l le ach i ng. Te s t s ample s a re typic a l ly ad m i n i s tere d
d i re c tly to the mu s cle ti s s ue b y i nj e c tion or s u rgic a l i mplantation . Site s ne e d to b e cho s en to m i n i m i z e
the lo s s o f fu nc tion or the p o s s ibi l ity o f p a i n from ner ve da mage c au s e d by mu s cle fibre ten s ion from the
i nj e c te d or i mpl ante d te s t s a mple . Site s shou ld b e ro tate d for rep e ate d do s e s tud ie s s i nce, for exa mp le,
non- aque ou s formu lation s may remai n as a dep o t for >2 4 h . T he u s e o f mu ltiple tre atment s ite s s hou ld
b e cle arly s p e c i fie d and j u s ti fie d .

ISO 1 0993 -1 1 : 2 0 1 7(E)
A.7 Intraperitoneal
Tests for systemic toxicity by the intraperitoneal route may be appropriate for devices with a fluid-path
or peritoneal cavity contact environment conducive to chemical leaching. This is also an appropriate
route when the extract should not be given intravenously, such as with non-polar oil extracts and
where particulates might be present. This route is pre ferable to filtering for an intravenous injection.
Test samples are typically administered directly to the peritoneal cavity. Dose frequency calculations
should consider that test articles administered by this route are absorbed primarily through the portal
circulation and therefore shall pass through the liver before reaching general circulation. Care should
be taken not to inject into the stomach or intestinal tract.
A.8 Intravenous
Tests for systemic toxicity by the intravenous route may be appropriate for devices with a direct
or indirect fluid-path or blood contact environment conducive to chemical leaching. Test samples
are typically placed in or administered directly to the vascular system. I f particulates are present,
delivery by the intraperitoneal route or sample filtration should be considered. For the evaluation o f
nanomaterials, nanomaterial dispersions themselves may be considered for intravenous administration.
Recommended dosage volumes and rates of administration for intravenous studies with the most
commonly used laboratory animal species are listed in Annex B.
Care should be taken to minimize the possibility o f extra vascular injection o f test sample. For injection
taking 5 min or more, consideration should be given to the use o f a butterfly needle or an intravenous
cannula.
A.9 Oral
Tests for systemic toxicity by the oral route may be appropriate for devices contacting the oral mucosa
directly or indirectly, or for products with other enteral application. Test samples are typically
administered by gavage. Experimental animals should generally be fasted prior to test sample
administration. The period o f fasting may range from hours to overnight, with the shorter periods for
animals with higher metabolic rates. Following the period of fasting, the animals should be weighed
and then the test sample administered in a single dose based on body weight. A fter the test sample has
been administered, food may be withheld for an additional 3 h to 4 h. Where a dose is administered
in fractions over a certain period, it may be necessary to provide the animals with food and water
depending on the length of the period.
A.1 0 Subcutaneous
Tests for systemic toxicity by the subcutaneous route may be appropriate for a device with a
subcutaneous contact environment conducive to chemical leaching. Test samples are typically
administered directly to the subcutaneous region by injection or by implantation. The use o f multiple
treatment sites should be clearly specified and justified.

ISO 10993-11:2017(E)
Annex B
(informative)
Dosage volumes
B.1 General
The principles of humane animal research require that all reasonable efforts be made to minimize or
Table B.1 are intended
el i m i nate a l l advers e phys iolo gic a l or p atholo gic a l e ffe c ts . T he va lue s l i s te d i n
to be informative and represent the maximum limits reported in the literature for single dose
administrations. These maximum values should not be taken as a recommendation in this document
but i nve s tigators shou ld apply upp er l i m its with regard to fac tors s uch as b o dy weight/s u r face are a,
rate o f ad m i n i s tration, nu mb er and fre quenc y o f ad m i n i s tration s , phys ic a l- chem ic a l a nd biolo gic a l
properties of the test sample, and animal strain. For repeated dose administrations attempts should be
made to m i n i m i ze the do s age volume wh i le ta ki ng i nto con s ideration the s e adj u s tment fac tors .
Table B.1 — Maximum single dosage volumes (ml/kg) for test sample administration
Subcutaneous Intramuscular Intraperitoneal Gavage Intravenous
Species
m l/ kg m l/ kg m l/ kg m l/ kg m l/ kg
Rat 20 1 20 50 40
Mouse 50 2 50 50 50
Rabbit 10
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Standard Sharing Group20and our chats 10
Dog 2 1 20 20 10
M on ke y 5 1 20 15 10
Re g u l atio n s o f i nd i vidu a l co u ntr ie s m ay s up er s e de the m a x i mu m vo lu me s l i s te d ab o ve . I ntra mu s c u l a r ad m i n i s tratio n s i n
ro de nts s ho u ld no t e xce e d 0 ,1 m l/s ite (mo u s e) a nd 0 , 2 m l/s i te (rat) , wh i le i ntrave no u s do s age vo lu me s s ho u ld no t e xce e d
1 m l/m i n .
B.2 Dosage volume references

See References [11],[12],[13],[14],[15],[16].

ISO 1 0993 -1 1 : 2 0 1 7(E)
Annex C
(informative)
Common clinical signs and observations
Table C .1 — Common clinical signs and observations
C linical ob ser vation Ob served sign I nvolved s ys tem(s)
D ys p ne a (ab dom i n a l b re ath i ng , ga s pi ng) ,
Re s pi rato r y ap no e a, c ya no s i s , tachyp ne a, no s tr i l C N S , p u l mo n a r y, c a rd i ac
discharges
D e c re a s e/i nc re a s e s om nolence , lo s s o f
Motor activities r i ghti ng , c ata lep s y, ata xi a, u nu s u a l lo co mo - C N S , s o m atomo to r, s en s or y,
neuromuscular, autonomic
tion, prostration, tremors, fasciculation
Convulsion C lon ic, to n ic, ton ic- clo n ic, a s phy xi a l , CNS, neuromuscular, autonomic,
opisthotonos re s p i rato r y
C o rne a l , r i ghti ng , myo tac tic , l i ght, s ta r tle

Re fle xe s C N S , s en s or y, autonom ic, neu romu s c u l ar,
re fle x
L ac r i m atio n , m io s i s , myd r i a s i s ,
Ocular signs e xop hth a l mo s , p to s i s , o p ac ity, i r iti s ,
conj u nc ti viti s , ch romo d ac r yor rhe a,

Autonomic, irritation
relaxation of nictitating membrane
Cardiovascular signs B radyc a rd i a, tachyc a rd i a, a r rhy th m i a,
vasodilation, vasoconstriction C N S , autonom ic , c a rd i ac , pu l mon a r y
Salivation Excessive Autonomic

Piloerection Rough hair Autonomic
Analgesia Decrease reaction C N S , s en s or y
Muscle tone H yp o ton i a, hyp er ton i a Autonomic

Gastrointestinal Soft stool, diarrhoea, emesis, diuresis, C N S , autono m ic, s en s o r y, GI mo ti l ity,
rhinorrhoea kid ne y
Skin O e dem a, er ythem a Tissue damage, irritation

ISO 1 099 3 -1 1 : 2 01 7(E)
Annex D
(informative)
Suggested haematology, clinical chemistry and urinalysis
measurements
D.1 Haematology
— Clotting potential (PT, APTT)

— Haemoglobin concentration
— Haematocrit
— Platelet count
— Red blood cell count
— White blood cell count
— WBC differential
D.2 Clinical chemistry
— Albumin
— ALP
— ALT
— AST
— Calcium
— Chloride
— Cholesterol
— Creatinine
— GGT
— Glucose
— Inorganic phosphorus
— Potassium
— Sodium
— Total bilirubin
— Total protein
— Triglyceride s
— Urea nitrogen

ISO 1 0993 -1 1 : 2 0 1 7(E)
— Additional enzymes, as scientifically appropriate

— Total immunoglobulin levels may be considered as an indicator for immunotoxicity
D.3 Urinalysis (timed collection, e.g. 1 6 h to 2 4 h)
— Appearance
— Bilirubin
— Glucose
— Ketones
— Occult Blood
— Protein
— Sediment
— Specific gravity or osmolality
— Volume
— Other scientifically appropriate tests i f test article is suspected to cause specific organ toxicity
(generally requires re frigerated sample collection)

ISO 1 099 3 -1 1 : 2 01 7(E)
Annex E
(informative)
Suggested organ list for histopathological evaluation
In addition to the histopathological evaluation, organs/tissues marked with an asterisk (*) below should
be weighed, with other organs weighed i f scientifically appropriate. The clinical and other findings may
suggest the need to examine additional tissues. Also, any organs considered likely to be target organs
based on the known properties of the test substance should be preserved.
Full histopathology should be carried out on the preserved organs and tissues o f all animals in the
control and highest dose group. These examinations, targeted to specific organs/tissues as necessary,
should be extended to animals of all other dosage groups if treatment-related changes are observed in
the highest dosage group.
— Adrenals*
— All gross lesions (including treatment sites)
— Aorta
— Bone marrow (femur, rib or sternum)
— Brain* (representative sections including cerebrum, cerebellum and pons)
— Caecum Get more FREE standards from Standard Sharing Group and our chats
— Colon
— Duodenum
— Epididymis*
— Oesophagus
— Eyes
— Gall bladder (if present)
— Heart*
— Ileum
— Jejunum
— Kidneys*
— Liver*
— Lungs and bronchi (preserved by inflation with fixative and then immersion)
— Lymph nodes (local to cover site o f administration and distant to cover systemic e ffects)
— Mammary gland (female)
— Muscle (skeletal)
— Nasal turbinates (for inhalation studies)
— Nerve (sciatic or tibial) pre ferably in close proximity to the muscle

ISO 1 0993 -1 1 : 2 01 7(E)
— O varie s *
— Pancreas
— Parathyroid
— P ituitar y
— Prostate
— Rectum
— S a l ivar y gl and s
— Seminal vesicles
— Skin
— Spinal cord
— Sple en*
— Sternum
— Stomach
— Te s te s *
— T hymus *
— T hyroid
— Trachea
— Uri nar y bladder
— Uteru s * (i nclud i ng cer vi x and oviduc ts)
— Vagina

ISO 1 099 3 -1 1 : 2 01 7(E)
Annex F
(informative)
Organ list for limited histopathology for medical devices subj ected
to systemic toxicity testing
F.1 General
M any me d ic a l device s employ com mon ly u s e d materi a l s d i fferi ng on ly i n the a mou nt or typ e o f chem ic a l
additives, processing or sterilization methods.

When a toxicolo gic a l ri s k a s s e s s ment of the device ex trac table s/ le achable s de term i ne s that a
bio comp atibi l ity/s a fe ty a s s e s s ment for p o tenti a l s ys tem ic e ffe c ts i s re qu i re d a re duce d h i s top atholo g y
eva luation may b e con s idere d . I n th i s mo del, a l i m ite d nu mb er o f p o tentia l ta rge t organ s/ti s s ue s a re
examined using a tiered approach.

F.2 Procedure
All tissues indicated in Annex E should be collected and preserved.

Li m ite d h i s top atholo gic a l a na lys i s shou ld b e comple te d for a l l T ier I organ s/ti s s ue s l i s te d i n Table F.1.
I f abnorma l or que s tionable fi nd i ngs are ob s er ve d i n
T ier I ti s s ue s , or i n the conc u rrent cl i n ic a l p atho lo g y
(cl i n ic a l chem i s tr y a nd haematolo g y) , pro ce e d to Tier I I (e xam i ne the fu l l l i s t o f organ s/ti s s ue s in
Annex E).
Table F.1 — O rgan list for limited his topathology
O rgan s ys tem O rgans/tiss ue (when s pecies applicable) of s ys tem T ier I tiss ues
C i rc u l ator y Heart, arteries, veins, capillaries, blood Heart

M o uth , s a l i va r y gl a nd s , o e s op h agu s , l i ver, s tom ach , ga l lb l adder,
Digestive pancreas, intestines (duodenum, transverse colon, ascending Liver

colon, de s cend i ng colon, i leu m, j ej u nu m, cae c u m, s igmoid colon) ,
rectum, anus
Endocrine H yp o th a l a mu s , p itu ita r y gl a nd , thyro id , p a rathyro id, ad ren a l s ,
pineal gland, pancreas Adrenals

E xc re tor y Kid ne ys , u re ters , b l adder, u re th ra, , s ki n , lu ngs , re c tu m Kid ne ys
I nte gu menta r y Skin, subcutaneous tissue, hair, nails Skin

Lymp h atic Lymph no de s , to n s i l s , adeno id s , thymu s , s p le en Spleen
Muscular Biceps, triceps, deltoids, gluteus, hamstring, tendons Muscle
Nervous B ra i n , s pi n a l co rd , ner ve s , p er ip hera l ner ve s , e ye s , e a rs Brain
Reproductive O varie s , fal lopi an tub es , uteru s , vagi na, mam mar y glands , te s tes ,
vas deferens, seminal vesicles, prostate, penis Testes, ovaries

Re s p i rato r y
diaphragm Lungs, bronchi
N o s e , n a s a l c avi tie s , p h a r yn x, l a r yn x, trache a , b ro nch i , lu n gs ,
Femur, humerus, radius, ulna, cranium, sternum, clavicle,

Skeletal fi b u l a , t i b i a , ve r te b r a e , Femur or sternum
s c a p u l a , p e l v i s , c o c c y x , p h a l a n ge s ,
marrow, cartilage, ligaments

Haematopoietic Bone marrow Femur, rib or sternum
Other Gross lesions including treatment site As observed

ISO 1 0993 -1 1 : 2 0 1 7(E)
Annex G
(informative)
Information on material-mediated pyrogens
Pyrogenicity is the ability o f a chemical agent or other substance to produce a febrile response.
Pyrogenic responses may be material-mediated, endotoxin-mediated, or mediated by other substances,
such as components of gram-positive bacteria and fungi. This document is concerned with material-
mediated pyrogenicity.
It is not necessary to test all new medical devices for in vivo pyrogenicity. However, materials containing
substances that have previously elicited a pyrogenic response, and/or new chemical entities where the
pyrogenic potential is unknown should be evaluated for material-mediated pyrogenicity. For medical
devices that may be used in a combination product, testing to satis fy the product pyrogenicity should
be considered. Endotoxin contamination may be a source o f a pyrogenic response, and should not be
con fused with a material-mediated pyrogenic response.
— Endotoxin-mediated pyrogenicity
This form o f pyrogenicity originating from biologically active endotoxin o f gram-negative bacteria,
which is usually a fever-inducing contamination in the manu facturing process o f medical devices, is
evaluated by measuring the amount o f endotoxin in the devices by an endotoxin-specific LAL (Limulus
Amebocyte Lysate) test without per forming a rabbit test (see Re ference [3]).
— Material-mediated pyrogenicity
This type o f pyrogenicity originates from non-endotoxin related factors. The following is a list o f
substances which are known to generate a pyrogenic response, without being endotoxins:
— endogenous pyrogens (e.g. IL-1, IL-6, TNF α, INF- γ);
— prostaglandin;
— inducers (e.g. polyadenylic, polyuridylic, polybionosinic and polyribocytidylic acids);
— substances disrupting the function o f thermoregulatory centres (e.g. LSD, cocaine, morphine);
— uncoupling agents o f oxidative phosphorylation (e.g. 4, 6-dinitro-o-cresol, dinitrophenol, picric acid);
— N-phenyl- β-naphthylamine and aldo- α-naphthylamine (the febrile mechanism is unknown);
— bacterial exotoxins (e.g. TSST-1, SEA, Spe F, Spe C);
— neurotransmitters (e.g. noradrenaline, serotonin);
— metals such as nickel salts, in some instances.
For detection o f material-mediated pyrogenicity, the rabbit pyrogen test, which has a wide range for
detecting pyrogenic activity, is currently recommended. Methods for per forming the rabbit pyrogen
test can be found in the United States Pharmacopoeia, the European Pharmacopoeia and the Japanese
Pharmacopoeia. The LAL test is not suitable for determining the pyrogenicity o f these substances.
Should other methods for detecting non-endotoxin pyrogenicity be developed, and become validated,
these will be considered for replacement of the rabbit test.
Ongoing developments are assays based on cytokine release by monocytes/macrophages which are
able to detect pyrogenicity related to components o f gram-negative and gram-positive bacteria and
fungi. These in vitro assays are not validated for material mediated pyrogenicity.

ISO 1 099 3 -1 1 : 2 01 7(E)
Annex H
(informative)
Subchronic rat — Dual routes of parenteral administration
H.1 General
Many devices requiring subacute/subchronic toxicity testing are implantable devices and thus the
most clinically relevant route o f exposure in the animal model is via implantation. However, when the
device is not intended for implant, exposure of the device via dosing of extracts is an option. Concurrent
parenteral administration of polar and nonpolar extracts can be an option.
Clinically, when a medical device is implanted or externally communicating, exposure to polar and
nonpolar leachables may be concurrent. One approach to assess toxicity is to inject both polar and
nonpolar extracts into the same animal. This exposure more closely simulates the clinical experience
o f total extractables exposure. This model may not be appropriate when there is a need to study the
administration routes separately. In that case Clause 6 should be considered.
Recommended dosing parameters for the dual routes of parenteral administration model are as
specified in the Table H.1.
Table H .1 — Recommended dosing parameters
D ose
Numb er of animals/
sex/group a Route Volume Frequency Rate
ml/kg b Study days d ml/min
6 Intravenous 10 Daily for 14 d ≤2
Intraperitoneal 5c 1, 4, 7, 10, 13 Slow bolus
a Vehicle control animals (6/sex) should be dosed similarly.
b Volumes are recommended.
c Sesame oil is preferred.
d Dosing days may begin on day 0.
H.2 Procedure
The test animals are dosed with the polar test sample extract, and the control animals are dosed with
polar vehicle, intravenously 7 d/week over the duration o f the study (i.e. 14 doses). For nonpolar test
samples the same test animals are dosed with the nonpolar test sample extract, and the control animals
are dosed with the nonpolar vehicle, intraperitoneally every third day over the duration o f the study
(i.e. 5 doses).
H.3 Dosage volume and frequency justification
H.3 .1 Intravenous
Table B.1 describes the maximum dosage volumes for test sample administration when a single
or a very limited number o f intravenous treatments are required. For daily-repeated or recurrent
administrations by any route the test sample volume should be reduced. LASA (see Re ference [17])
recommends a maximum intravenous dosage volume o f 5 ml/kg for a bolus injection in the rat carried
out over a relatively short period o f time (less than 1 min), and for once daily dosing on a routine basis

ISO 1 0993 -1 1 : 2 0 1 7(E)
(i nj e c tion rate ≤ 2 m l/m i n) . For rep e ate d i ntravenou s ad m i n i s tration o f me d ic a l device ex trac ts a do s e
volume o f 10 m l/ kg i s con s idere d u n l i kely to c au s e u ndue s tre s s i n the an i ma l s , s e e Re ference [ 13].

H.3 .2 Intraperitoneal
Table B.1 de s c rib e s the ma xi mu m do s age volume s for te s t s ample ad m i n i s tration when a s i ngle or a ver y
l i m ite d nu mb er o f i ntrap eritone a l tre atments a re re qui re d . C u rrent exp erience i nd icate s that 5 m l/ kg
o f s e s a me oi l e x trac t given i nterm ittently i s wel l tolerate d . Su ffic ient a ne cdo ta l evidence s ugge s ts that
a p eritone a l re s idua l volu me (PRV ) o f non-aque ou s i nj e c tate s o f 5 m l/ kg to 10 m l/ kg may p ers i s t for up
to th re e d ays . C on s e quently, for rep e ate d i ntrap eritone a l ad m i n i s tration o f nonp olar me d ic a l device
ex trac ts , when ad m i n i s tere d conc u rrent with an i ntravenou s i nj e c tion o f 10 m l/ kg , a do s e volu me
o f 5 m l/ kg i s con s idere d un l i kely to c au s e u ndue s tre s s i n the an i ma l and repre s ents an accep tab le
protracted exposure volume for nonpolar extracts.

S evera l comp l ic ation s by the i ntrap eritone a l route o f ad m i n i s tration a re wel l do c u mente d . T he s e
i nclude ble e d i ng at the i nj e c tion s ite, p ara lytic i leu s due to s ub s tance i nj e c te d , laceration o f ab dom i na l
orga n s , p eritoniti s , and i nj e c tion i nto the ga s troi nte s ti na l trac t or bladder. I n that regard, the fre quenc y
o f errone ou s i ntrap eritone a l i nj e c tion s by s ki l le d i nve s tigators ha s b e en rep or te d to ra nge from 11 %
to 2 0 % (s e e Re ference [ 18]). In view of this, and with consideration of the PRV and the potential for
i nc re a s i ng i ntrap eritone a l i nj e c tate volu me with to o fre quent do s i ng , a th rice we ekly ad m i n i s tration
s che du le is con s idere d u n l i kely to c au s e u ndue s tre s s in the an i ma l and repre s ents an accep tab le
pro trac te d exp o s u re fre quenc y for non-aque ou s i nj e c tate s .
G enera l a s p e c ts o f s tudy de s ign a re covere d i n Clause 6.

ISO 10993-11:2017(E)
Bibliography
General
[1] ISO 10993, Biological evaluation of medical devices
[2] ASTM F619-03, Standard Practice for Extraction of Medical Plastics
[3] AAMI/ST72 , Bacterial Endotoxin — Test methods, routine monitoring, and alternatives to
batch testing
[4] U.S./EPA PB 86/108958 and 89/124077

[5] U.S./FDA Toxicological principles for the sa fety assessment o f direct food additives, 1982
[6] U.S. Code of Federal Regulation 1500.40: Method of Testing Toxic Substances
[7] United States Pharmacopoeia 26: Biological Reactivity Tests, In Vivo; The National Formulary 21,
Rockville, MD; Pharmacopoeial Convention, 2003, pp. 2028-2032
[8] European Pharmacopoeia. Eighth Edition, 2014
[9] MHLW Notification by Director, OMDE, Yakushokuki-hatsu 0301 No. 20, March 1, 2012. Basic
Principles o f Biological Sa fety Evaluation Required for Application for Approval to Market
Medical Devices
[10] OECD. Series on Testing and Assessment No. 129: Guidance Document on Using Cytotoxicity
Tests to Estimate Starting Doses for Acute Oral Systemic Toxicity Tests
Dosage volume references
[11] H ull R.M. Guideline limit volumes for dosing animals in the preclinical stage o f sa fety
evaluation. Human and Environmental Toxicology. 1995, 14 pp. 305–307
[12] D erel anko M.J., & H ollinger M.A. CRC Handbook o f Toxicology. CRC Press, NY, Second
Edition, 2001, pp. 98.
[13] D iehl K.-H., H ull R., M orton D., P f ister R., R abem ampi anina Y., S mi th D. Vidal , J.–M, Van
D e Vorstenbosch . A good practice guide to the administration of substances and removal of
blood, including routes and volumes. J. Appl. Toxicol. 2001, 21 pp. 15–23
[14] M orton D. Effects of infusion rates in rats receiving repeated large volumes of intravenous
saline solution. Lab. Anim. Sci. 1997, 47 pp. 656–659
[15] R ichmond J.D. Dose limit volumes: The United Kingdom view — past and present. Presented
at the Humane Society o f the United States — Refinement in Toxicology Testing: Dosing Data:
Volume and Frequency, March 14, 1999, New Orleans, LA
[16] M orton D.B. Refining procedures for the administration o f substances. Report o f the
BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement. Lab. Anim. 2001, 35
pp. 1–41
[17] Laboratory Animal Science Association (LASA) Good Practice Guidelines: Administration o f
Substances (Rat, Mouse, Guinea Pig, Rabbit) – Series 1/Issue 1 – October 1998
[18] N ebendahl K. Routes o f Administration. In: The Laboratory Rat: A Volume in Handbook o f
Experimental Animals, (K rinke G.J. ed.) . Elsevier Ltd, 2000, pp. 463–83.
[19] G aines Das R., & N orth D. Implications o f experimental technique for analysis and
interpretation o f data from animal experiments: outliers and variability resulting from failure
o f intraperitoneal injection procedures. Lab Anim. (NY). 2007, 41 (3) pp. 312–320
ISO 1 0993 -1 1 : 2 01 7(E)
[20] C ori a-Avil a GA, & G avril a AM BA1, S h ann Mé nard S, I sm ail N, P faus JG. Cecum location in
rats and the implications for intraperitoneal injections. Lab. Anim. 2007, 36 (7) pp. 25–30
[21] OECD. (1981 – 2013): http://www.oecd-ilibrary.org/environment/oecd-guide lines- for-the-
testing-of-chemicals-section-4-health-effects_20745 788

ISO 1 0993 -1 1 : 2 01 7(E)
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INTERNATIONAL ISO

Biological evaluation of medical

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ii © ISO 2017 – All rights reserved

1 Scope .................................................. ................................................... ................................................... ................................................... ...................... 1

2 Normative references .................................................. ................................................... ................................................... .............................. 1

3 Terms and definitions .................................................. ................................................... ................................................... ............................. 1

6.4 Final report ................................................... ................................................... ................................................... .................................... 15

iv © ISO 2017 – All rights reserved

© ISO 2017 – All rights reserved v

device’s materials and its intended clinical application.

Fi na l ly, toxicolo g y i s an i mp er fe c t s c ience . T he outcome o f any s i ngle te s t s hou ld no t b e the s ole b a s i s

vi © ISO 2017 – All rights reserved

Biological evaluation of medical devices —

— ISO Online browsing platform: available at http: //w w w. i s o . org/obp

i nd i vidu a l to a ra n ge o f do s e s . T he s e cond typ e i s the d i s tr ib utio n o f re s p on s e s o f a p op u l atio n o f i nd i vidu a l s to

© ISO 2017 – All rights reserved 1

N o te 1 to entr y: S ys tem ic toxic i ty re qu i re s ab s or p tio n a nd d i s tr ibution o f a toxic a nt fro m i ts entr y p oi nt to a

distant site at which deleterious effects are produced.

test sample for 24 h

p er io d m ay a l s o b e de s c r ib e d a s a s ho r t- ter m rep e ate d e xp o s u re s ys tem ic toxic i ty s tudy. T he s ele c tio n o f ti me

o f o ther s p e c ie s . Sub ch ro n ic i ntraveno u s s tud ie s a re genera l l y de fi ne d a s tre atment du ratio n s o f 14 d to 2 8 d fo r

part of the life span

chemical testing or evaluation

2 © ISO 2017 – All rights reserved

4.4 Animal care and husbandry

© ISO 2017 – All rights reserved 3

4.5 Size and number of groups

4.5 .1 Size of groups

Study type Rodent Non-ro dent

rodent group size is recommended. The number of animals

4.5 .3 Treatment controls

4 © ISO 2017 – All rights reserved

4.6 Route of exposure

Guidance on sample preparation and stability is given in ISO 10993-12.

4.8.1 Test sample administration

© ISO 2017 – All rights reserved 5

4.9 Body weight and food/water consumption

4.11 Clinical pathology

6 © ISO 2017 – All rights reserved

Table 2 — Summary of observations

Ob ser vation Acute Sub acute/s ub chronic C hronic a

4.1 3 Study designs

© ISO 2017 – All rights reserved 7

5 .2 .2 .2 Number and sex

The number and type

5 .2 .2 .3 Housing and feeding conditions

Dose levels shall be as specified in 4.8.

8 © ISO 2017 – All rights reserved

5.2.4 Body weights

5.2.5 Clinical observations

5.2.6.1 Clinical pathology

5.2.6.2 Gross pathology

© ISO 2017 – All rights reserved 9

10 © ISO 2017 – All rights reserved

2) o ther identi fic ation data .

c) Extraction solvent or vehicle (if appropriate):

2) number, age and sex of animals;

4) weights at s tudy i niti ation .

homo geneity, i f appropriate;

3) details of the administration of the test sample;

5) de ta i l s o f fo o d, water and b e dd i ng qua l ity.

2) b o dy weight/ b o dy weight change;