Part 1

Biological Risk Management: Hazard Identification and

Derivation of Tolerable Intake Values
ISO 10993-17:2023
Toxicological Risk Assessment of Medical Device Constituents

Presenters: Alan Hood, Todd Kennedy, Sherry Parker

January 11, 2024

 ISO 10993-17:2023
Toxicological Risk Assessment of Medical Device Constituents

Part 1 Topics

A - Toxicological risk assessment within the biological

evaluation process

B - Toxicological Information, Hazardous Constituents, TSL,

Carcinogens

C - Derivation of Tolerable Intake Values

4
 Topic A
Toxicological risk assessment within the biological
evaluation process

Alan Hood, PhD

Office of Product Evaluation and Quality (OPEQ)
Center for Devices and Radiological Health (CDRH)
U.S. Food and Drug Administration (US FDA)

Roles in ISO Standard Development Process:

US AAMI BE WG 11 Co-Chair
ISO TC 194 WG11 Convenor
5
Disclaimer

The findings and conclusions in this presentation have not been formally
disseminated by the Food and Drug Administration, are the views of the
authors, and should not be construed to represent any agency
determination or policy.
The mention of commercial products, their sources, or their use in
connection with material reported herein is not to be construed as either an
actual or implied endorsement of such products by Department of Health
and Human Services.

6
 Topic A
Toxicological risk assessment within the biological evaluation process

Parts of ISO 10993-17:2023 that are covered in this presentation

• Process of revising ISO 10993-17

• Clause 3. Terms and Definitions

• Clause 5. Toxicological risk assessment within the biological evaluation process

Note: FDA/CDRH partially recognizes ISO 10993-17:2023. For specific text not recognized, see
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/detail.cfm?standard__identification_no=44811

7
Topic A
Process of revising ISO 10993-17:2023
Phase Year Description
WD 2016 In October 2016, ISO TC 194 WG11 experts met in Annapolis, Maryland and discussed the need to
Study expand the scope of the current ISO 10993-17 to include toxicological risk assessment of medical
device constituents. Because ISO TC 194 WG14 update of 10993-18 includes when a toxicological
risk assessment should be conducted, WG11 agreed that expansion of ISO 10993-17 is needed and
formed a writing group to create the framework that describes the new revision.

NWIP 2018 In April 2018, ISO TC 194 WG11 experts agreed that a proposed working draft (WD) document is
adequate for preparing and submitting a new work item proposal (NWIP). The proposal was to
update the document to establish a common medical device constituent toxicological risk
assessment approach, including common requirements and criteria.
WD 2019 In October 2019, moving the working draft (WD) document to the committee draft (CD) stage was
initiated. Project officially began October 2020.
CD 2021 In October 2021, moving CD document to the draft international standard (DIS) stage was initiated.
DIS 2022 In August 2022, moving the DIS document to final DIS (FDIS) stage was initiated.
FDIS 2023 In August 2023, the FDIS document was submitted to ISO/CEN for review and published in
September 2023.
8
Topic A
Clause 3. Terms and Definitions (key)
Clause Term Definition Related Clauses
3.11 Identified constituent (3.4) for which molecular structure 6.2.1 (application of in silico analysis)
Constituent information is complete 6.2.2 (application of TSL, also see Annex B)
Note 1 to entry: The identity of a constituent can be
obtained by information gathering or non-targeted 6.2.4 (application of TTC or identification of an
or targeted analytical approaches as described in ISO analogue)
10993-18. E.2 (exposure dose estimation based on
release kinetics information)

Clause Term Definition Related Clauses

3.27 Total amount of a constituent (3.4) present in, or 6.2.2 (when the quantity represents
Quantity that can be extracted from, the medical device cumulative exposure and compared to TSL)
(TQ) Note 1 to entry: The total quantity is expressed in E.3 (when estimating worst-case exposure
microgram (μg). dose based on maximum release and the
Note 2 to entry: The constituent’s total quantity and quantity represents cumulative exposure)
its release rate (or kinetics) influence the maximum
duration that an individual can be exposed to the
constituent (3.4)[11].
9
Topic A
Clause 3. Terms and Definitions (key)
Clause Term Definition Related Clauses
3.32 Worst-Case exposure dose (3.7) that is a maximum value for a Clause 8 (requirement that worst-case
Estimated specified intended clinical-use scenario estimated exposure dose is based on
Exposure Note 1 to entry: EEDmax is based on the selection of the full worst-case conditions).
Dose range of intended clinical use scenarios, specific clinical use 9.2 (requirement that MoS is based on
(EEDmax) condition or assumption related to the intended clinical worst-case estimated exposure dose)
scenario (see Annex E for additional information).
Annex E (how to determine worst-case
Note 2 to entry: Specific clinical use conditions or
assumptions used to establish worst-case estimated estimated exposure dose for different
exposure dose do not include deliberate misuse of a medical types of chemical data)
device that is not reasonably foreseeable or that results in
different harm to health (3.8).

The remaining terms and definitions in Clause 3 are important and necessary to apply the standard as
intended by ISO / TC 194.

10
Topic A

Clause 5
Toxicological risk assessment within the biological evaluation
process
The toxicological risk assessment (TRA) approach should:
• Be systematic (5.1.1)
• Align with applicable risk management principles of ISO 14971
o Hazard identification (5.1.2)
o Risk estimation (5.1.3)
• Align with ISO 10993-1 biological evaluation process (5.2)
• Figure 1. Toxicological risk assessment within the biological evaluation process
• Figure 2. Critical toxicological risk assessment activities

11
Topic A
Figure 1. Toxicological risk assessment within the biological evaluation process

“Identity/quantity adequate?” indicates not all constituents could be addressed

in the TRA (e.g., a reportable extractable with no identity information), and
additional steps in accordance with ISO 10993-1 would be considered, such as:
analyze, evaluate or control the risk (e.g., identity information that permits
identification of hazardous constituents, see clause 6 for requirements,
recommendations and guidance).

“Derive TCL/TI or apply TTC (if applicable)” indicates multiple types of

thresholds for a constituent may be necessary when the same or different
constituents elicit different types of harms that are relevant to device intended
use.

“Derive MoS (if applicable)” indicates calculating an MoS may not be necessary
for all identified constituents, see Figure 2. Calculating and reporting MoS would
be necessary when TSL is not used, and a relevant PoD is available. The
document requires justifying and documenting in the report how the
toxicological risk(s) of constituents are addressed.

“Further analyze” indicates additional biological or chemical information may be

necessary, for example, conduct applicable biological test or identify whether a
medical device constituent is a hazardous substance(s) or demonstrate that
exposure to the constituent will be at a tolerable level or control the risk, or if
risk control is not practical then consider benefit-risk. 12
Topic A
Figure 2. Critical toxicological risk assessment activities

“Relevant harms or TQ > TSL?”, “Is TSL used?”, and “Quantity (i.e., TQmax) < TSL?”
indicate when calculating and reporting an MoS for a reportable constituent
would not be required, provided that the justification used addresses applicable
requirements.

“Worst-case exposure dose < TTC?” indicates when the standard does not require
calculating and reporting an MoS for a specific constituent.

“Tox. risk acceptance criteria met?” means

• the worst-case exposure dose DOES NOT exceed the constituent specific TI
value (i.e., MoS >1 where MoS = TI ÷ EEDmax) AND
• the TI and EEDmax values deliberately overestimate (i.e., lower MoS) the
probable true risk.

“Tox risk acceptance criteria met? No” indicates the risk management process
DOES NOT STOP. Instead, the risk of the identified hazard should be further
analyzed (if feasible), or alternatively, evaluated and mitigated. If mitigating the
risk is not practicable, then benefit-risk considerations may be useful. The
standard requires justification and documentation of the risk management
approach that is used.
13
Topic A Clause 5
Toxicological risk assessment within the biological evaluation process

14
Topic A
ISO 10993-17:2023 - Errors

• Example 6, Annex B,

Should read...
10 is the SF where 50 500 cm2 is the maximum device surface area, in cm2, that is in contact with
the body divided by the 50 cm2 device surface area extracted.

• Table B.1, 2nd Column,

Should read...
Period of assumed exposure TTC D TSL
to the constituent g/d µg/d d µg
d

15
 Topic B
Toxicological Information, Hazardous Constituents,
TSL, Carcinogens

Todd Kennedy, PhD DABT

WL Gore & Associates, Inc

Roles in ISO Standard Development Process

US AAMI BE WG 11 Expert
ISO TC 194 WG11 Expert

16
 Topic B
Toxicological Information, Hazardous Constituents, TSL,
Carcinogens
Parts of ISO 10993-17:2023 that is covered in this presentation

• Constituent specific toxicological information (6.1)

• Identification of hazardous constituents (6.2.1)

• Toxicological screening limit (6.2.2)

• Identification of human carcinogens or suspected human

carcinogens (6.2.3)

17
Topic B

Constituent specific toxicological toxicological

Information (6.1)
Description of harms to health that can be addressed in the TRA

Harm TCL TSL TI TTC

Irritation X
Systemic toxicity X X X
Genotoxicity X X X
Carcinogenicity X X X
Reproductive X X X
Toxicity
Developmental X X X
Toxicity
*Other endpoints, such as sensitization, can be addressed but must be justified. 18
Topic B

Identification of Hazardous Constituents (6.2)

 Requirements, recommendations, and guidance:
 Obtaining, evaluating, and documenting
toxicological information about constituents
 Permits in silico models for an identified constituent
(must be validated)
 Specific exposures and relevance to medical
device use

19
Topic B
Toxicological Screening Limit (TSL)
(6.2.2 and Annex B)
cumulative exposure dose (3.7) to an identified constituent (3.11) over a
specified time period that is without appreciable harm to health (3.8)

Note 1 to entry: TSL is expressed in microgram per individual

exposed.

TSL (µg) ≠ AET (µg/ml) TSL (µg) ≠ TTC (µg/day)

TSL (µg) ≠ DBT (µg/day)

20
Topic B
Background of TSL
 TSLs are TTCs expressed as cumulative doses over a specified time period
 TTCs are typically expressed as daily exposure doses, µg/day
 TTCs multiplied by days of exposure duration (TTC x days) give the TTC in
cumulative exposure dose, µg
 Cannot exceed the daily exposure in µg/day if less than corresponding cumulative TTC

Medical Device contact Limited Prolonged Long-term

Category (<24 h) (24 h to 30 days) (> 30 days)

TTC Exposure Duration Limited Prolonged Long-term Long-term Long-term

Category (<24 h) (24 h to 30 days) (> 1 month to 1 (> 1 year – 10 (>10 years)
year) years)
TTC, µg/day 120 120 20 10 1.5

Exposure duration, day 1 2 31 366 3650

Cumulative TTC, µg 120 240 620 3660 5475

TSL = Toxicological Screening Limit TTC = Threshold of Toxicological Concern TQ = Total Quantity 21
Topic B

Background of TSL
TTC Exposure Duration Limited Prolonged Long-term Long-term Long-term
Category (<24 h) (24 h to 30 (> 1 month to 1 (> 1 year – 10 (>10 years)
days) year) years)
Cumulative TTC, µg 120 240 620 3660 5475

 Lowest Cumulative TTC is 120 µg

 If Total Quantity (TQ in µg) is less than 120 µg, then:
 the quantity is insufficient to exceed the cumulative TTC for any exposure duration
AND
 Therefore, risk of adverse effects is considered negligible
 Therefore, 120 µg is a cumulative threshold below which the risk of
adverse systemic effects of the TQ is considered negligible.

TSL = Toxicological Screening Limit TTC = Threshold of Toxicological Concern TQ = Total Quantity 22
Topic B

Toxicological Screening Limit (TSL) (6.2.2 and Annex B)

Optional tool to reduce the work required to perform a TRA
• When TSL can be applied:
• When total Quantity (TQ) of an identified
constituent is reported
• When the TQmax value represents the
cumulative exposure dose, see clause
6.2.2 for guidance

• Key requirements:
• TSL must be compared to TQmax
• TQmax accounts for the duration of
exposure, number/quantity of devices
extract, and number/quantity of devices
that contacts the body
• See clause 6.2.2 for remaining
requirements 23
Topic B

Toxicological Screening Limit (TSL) (6.2.2 and Annex B)

TSL is not applicable to the following:

 long-term devices used in patients < 6 months of age

 cohort of concern or excluded substances

 volatile compounds of gas pathways devices

 harms not protected by TTC values

 single-use (disposable) medical devices that are

repeatedly used and cumulative duration of body
contact is long-term

24
Topic B

Toxicological Screening Limits (TSL) (Annex B)

Medical device Periods of assumed exposure to constituent
contact
duration 1d ≤30 d >30 d

Limited NA
NA
Prolonged 120 µg 120 µg
Long-term 600 µg

TSL = Toxicological Screening Limit

25
Topic B

Calculating TQmax (B.3)

TQ is the reported total quantity of an identified
extractable from an exhaustive or exaggerated
extractables study
 May need adjustment based on the number or amount
of devices in the extractables study compared to worst-
case clinical exposure

 Use Scaling Factor (SF) to make adjustment

 Example – if one device was extracted, but two devices can be
used worst-case clinically, then SF = 2

 TQmax = TQ x SF

 TQmax = 50 µg/device x 2 devices = 100 µg

TSL = Toxicological Screening Limit SF = Scaling Factor 26

Topic B

Application of TSL (6.2.2, Examples in B.3)

 Compare TSL to TQmax

 If TQmax < TSL, then the toxicological risk is negligible for that
extractable

 If TQmax > TSL, then exposure dose shall be estimated and evaluated
as described in Clauses 7, 8, 9, and 10

TSL = Toxicological Screening Limit TQ = Total Quantity TI = Tolerable Intake 27

Examples (Annex B)
Example 1 - Limited or prolonged contact: when 100 µg of an
identified constituent is extracted from a single medical device
and 1 device contacts the body for less than or equal to 30 d
(not repeatedly used).

TSL≤30 d = 120 µg/d x 1 d = 120 µg

TQmax = 100 µg x 1 = 100 µg

Short-term exposure to the constituent is a negligible

toxicological risk because TQmax is less than TSL≤30 d
Examples (Annex B)
Example 2 – Limited or prolonged contact: when 100 µg of an
identified constituent is extracted from a single medical device
and 2 devices contact the body for less than or equal to 30 d
(not repeatedly used)

TSL≤30 d = 120 µg/d x 1 d = 120 µg

TQmax = 100 µg x 2 = 200 µg

Short-term exposure to the constituent can present a

toxicological risk because TQmax is greater than TSL≤30 d
Examples (Annex B)
Example 3 – Long-term contact: when 300 µg of an identified constituent
is extracted from a single medical device and 1 device contacts the body
for long-term (i.e. greater than 30 d)

TSL≤30 d = 120 µg/d x 1 d = 120 µg

TSL>30 d = 20 µg/d x 30 d = 600 µg

TQmax = 300 µg x 1 = 300 µg

Short-term exposure to the constituent can present a toxicological risk

because TQmax is greater than TSL≤30 d
Long-term exposure to the constituent is a negligible toxicological risk
because TQmax is less than TSL>30 d
Topic B

Cancer TI Derivation (6.2.3 and C.3)

 Applies to human and suspected human carcinogens
 Acceptable lifetime cancer risk of 1 in 100,000 (10-5)
 Two approaches permitted (most appropriate for genotoxic carcinogens)
 Cancer slope factor approach
 1 x 10-5/CSF = TI equivalent to 1 in 100,000 lifetime cancer risk (Cancer Risk Specific Dose
(CRSD)

 TD50 approach
 TD50/50,000 = TI equivalent to 1 in 100,000 lifetime cancer risk (CRSD)

 Other approaches are permitted if justified and documented. 31

 Topic C
Derivation of Tolerable Intake Values

Sherry Parker, PhD

SParker Toxicology Consulting LLC

Roles in ISO Standard Development Process

US AAMI BE WG 11 Co-Chair
ISO TC 194 WG11 Expert

32
 Topic C
Derivation of Tolerable Intake Values

Parts of ISO 10993-17:2023 that is covered in this presentation

• Clause 6.2.4. Selection of the point of departure

• Clause 7. Tolerable contact level, tolerable intake and threshold of

toxicological concern

• Annex C. Derivation of constituent TI or TCL for select endpoints

• Annex D. Typical Assumptions for Biological Parameters

33
Topic C

Requirements
 When a constituent specific POD is available, the selected POD and source (i.e.,
primary health effect data, supporting data or secondary health effect source)
shall be documented
 The most critical (e.g., the lowest) clinically relevant POD shall be selected.
 When toxicological information is assessed to be inadequate or absent for an
identified constituent, the use of TTC (Clause 7.2) or toxicological data from a
structural analogue (also known as read-across approach), shall be justified and
documented

Additional Guidance on
Guidance on Evaluating
Selection of POD included in
Data Quality in Annex A
Clause 7.1

34
Topic C

Use of Read-Across: Useful Criteria for Identifying

Analogue

When toxicological information is inadequate or absent for

identified constituent

Select an analogue based on following

• Similar molecular structure (Tanimoto/similarity score, Fingerprints
can be useful)
• Similar physical and chemical properties
• Similar biological properties (e.g., metabolic pathways)

Requirements

• Selection of a structural analogue shall be justified and

documented. Alternatively, TTC can be used to address
genotoxicity, carcinogenicity, systemic toxicity, or reproductive or
developmental toxicity as described in 7.2 35
Topic C

7 Tolerable contact level, tolerable intake

and threshold of toxicological concern

7.1 Derivation of TCL and TI

36
Topic C

Deriving a TI or TCL…first determine if POD is available

 When available, a constituent’s POD is used to derive a TCL or TI value for each
constituent. The TCL (i.e., for irritation) or TI (i.e., for genotoxicity, systemic toxicity,
carcinogenicity, or reproductive or developmental toxicity) used shall account for
the duration for which constituent exposure is assessed.
 When multiple NILs or NOAELs are available that apply to the same harm and
same clinically relevant exposure scenario, the highest NIL or NOAEL can be used
to derive the TCL or TI, respectively. When toxicological data are of mixed quality,
the TCL or TI shall be based on the study with the highest quality data
 For different harms, lowest POD shall be used.

Annex C: Derivation of constituent TI or TCL for select endpoints

Annex D: Contains biological information that may be useful (e.g., converting the units of a
selected PoD when route-to-route differences exist). 37
Topic C

When a threshold for a constituent is available for other

applications (e.g., pharmaceutical, food, occupational,
environmental)…..
1. applicability of the threshold for the duration and type of medical device body
contact shall be justified and documented
2. additional UF(s) should be applied when the approach used to derive the
threshold does not address all of the sources of uncertainty that reflect the
circumstances of exposure applicable to the intended use of the medical
device

Thresholds for other

purposes may not be
directly applicable to
medical devices 38
Topic C
Annex C
Deriving a TI (non-cancer, or cancer) or TCL For Select Endpoints
Non-Cancer TI, Clause C.2

In absence of data, use

Point of departure Threshold of
TI Shall Account for…
(POD) Toxicological Concern
(TTC); Clause 7.2
• Benchmark dose • Most Sensitive Patient • See Technical
(BMDL), or a NOAEL or Population (for Device Specification TS 21726 -
LOAEL or other value Contact) 2019
• Uncertainty of the
data and
extrapolation to
human exposure

Note: Where relevant dose-based threshold has been determined by an expert committee or regulatory
Agency for non-medical device use; it can be adapted by use of uncertainty factors
39
Topic C

Application of Uncertainty Factors

Default UFs:
Determination of Uncertainty  UF(TI)1: 10 for Interspecies Differences
Factors (UF): among humans (unless otherwise
Clause C.2.2 justified)
 For preterm, neonate and very young
Value of each UF shall be infants (i.e., 6 months or younger),
documented, with justification additional UF of 3 shall be applied
 UF(TI)2: 10 for Intraspecies Differences
(unless otherwise justified)

For Intraspecies variation, a UF can be less than 10 when supported by human data

For Interspecies differences, a UF can be less than 10 when toxicity and toxicokinetic
data support similarity 40
Topic C

Additional Uncertainty Factors: UF(TI)n

Considerations for each is included in text

41
Topic C

Additional Uncertainty Factors: Route to Route (C.2.2.4.1)

 For extrapolation from inhalation to parenteral routes, default UF=10

 Lower or higher UFs can be applied when the extent of absorption is known (e.g., higher absorption
can be higher for more volatile organic chemicals vs. non-volatile organic chemicals and metals
 For inhalation to oral, UF of 1 can be applied
 For oral to parenteral, oral bioavailability data can be used (shall be justified with supporting data)
 100 if oral bioavailability is <1%
 10 if oral bioavailability is ≥1% and <50%
 2 if oral bioavailability is ≥50% and <90%
 1 if oral bioavailability is ≥90%
 Oral POD can be extrapolated by multiplying by the percent of oral bioavailability
 In absence of bioavailability, default UF of 10 can be used

42
Topic C

Additional Uncertainty Factors: Exposure Duration

(C.2.2.4.2)

 For subchronic to chronic exposure extrapolation,

default UF=6 (unless otherwise justified)

• For subacute to chronic exposure extrapolation, default

UF=10 (unless otherwise justified)

 UF 10 should be applied when dose-response curve is

shallow or unknown

 Higher UFs may be considered when toxicity increases

over time and constituents bioaccumulate
43
Topic C

Additional Uncertainty Factors: POD, Data Applicability, and Data

Quality (C.2.2.4.3)

 Consider uncertainty in applying data from an analogue

(read-across) based on extent of structural/biological similarity
 Default UF of 1 for high quality studies; 10 for studies with
reduced reliability or relevance
 Examples of when default UF 10 for data quality and relevance
can be applied
 Absence of clinically relevant tox data pertaining to patient population, e.g.,
repro/dev tox for device used in pregnant women
 POD obtained from underpowered study (limited number/sex/parameters)

44
Topic C

MF = UF(TI)1 × UF(TI)2 × UF(TI)n

The application of a large MF

(e.g., >10 000 for the general
Modifying Factor population) can overestimate a
toxicological risk
(C.2.3)
In these cases, toxicological risk
shall be assessed by applying TTC
in accordance with 7.2, or further
analyse or control the
toxicological risk
45
Topic C

Derivation of a TCL for irritation (C.4)

 TCL (µg/cm2)= NIL / MFTCL (NIL=non-irritating level in µg/cm2)

 Uncertainty Factors
 Intraspecies variation UF(TCL)1. Default of 10 unless otherwise justified (but UF of 3 to 9 can be used if
justified)
 Interspecies variation UF(TCL)2. Default of 10 unless otherwise justified
 Uncertainty from quality or relevance of experimental data UF(TCL)n
 When a MIL is used, default UF of 3 shall be applied unless otherwise justified
 UF of 9 applied when conclusions are drawn based on poorly designed or executed study, or when the
amount of relevant constituent specific irritation is limited

 In most cases, an overall modifying factor of 30 or less should be sufficient

but can be larger when non-irritating concentrations have not been
established
46
Topic C

Annex D
Typical Assumptions for Biological Parameters
 For Humans (examples)
 70-year lifespan
 20 m3/24 h day air intake (adult)
 70 kg body mass for adult men; 60 kg for adult women, or unisex (lower body mass, 50 kg or
lower can be used if more conservative approach necessary)
 10 kg for children (>1 year to ≤16 years of age); 3,5 kg for infants (<1 year); 1,5 kg for very
low birthweight infants; or 0,5 kg for very low birthweight neonates (e.g., preterm neonate);
 NOTE: In the medical devices intended use is for a wide range of general patients, the use
of infant mass (3,5 kg) is sufficiently conservative to calculate the EEDmax for infants and the
general population.

Assumptions for other species are also included (e.g., can be helpful calculate
a NOAEL in mg/kg/day from a POD in drinking water or feed in animals) 47
QUESTIONS?

48
Thank you for participating!
Please attend Part 2 of this webinar series on
Wednesday, January 24, at 2:00 PM EST