Non-testing / ITS

Dinant Kroese

TNO| knowledge for businessChemical Safety assessment scheme

ITS / NT

From REACH Guidance on information
requirements and CSA – Part D
2NT - ITS, Japan 09

CONTENTS

3

1.

ITS & Non-Testing (NT) data

2.

Existing Guidance & Tools for generating NT data3.

Our experience4.

Developments for generating NT data

5.

Exposure-based Waiving

6.

Final Conclusions

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1. ITS & Non-testing data
CSA steps (Annex VI)

41.

Gather and share available information

2.

Consider information needs

3.

Identify information gaps

4.

Generate new data / propose testing strategy

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ITS:“Efficient Information Gathering Strategy”
Human data

Step 1: Gather all available Testing and Non-Testing information(Q)SAR

In vitro

ExposureGrouping &read across5

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All available Testing and Non-Testing information
Human data
Human data

Non-Testing information(Q)SAR models(Q)SAR

InIn
vitro
vitro

Grouping& read acrossExposure
Exposure
Exposure6

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General rules for adaptation of Standard (test) Requirements
Annex XI
1. Testing does not appear scientifically necessary
•
•
•
•
•

Use of existing data: PC, non-GLP etc, Historical human data
Weight of evidence
In vitro methods
Quantitative or Qualitative Structure Activity Relationships ((Q)SAR)
Grouping of substances and read-across approach

2. Testing is technically not possible
3. Substance-tailored exposure-driven testing7

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ITS: Information Gathering Strategy
Human data

Step 1: Gather all available Testing and Non-Testing information(Q)SAR
If not sufficient(for C&L and RA)

In vitro(Is Testing technically possible?)

Step 2: Is Exposure-Based Waiving an option?
If not possible

Exposure

Step 3: Perform / Propose Testing as last resort!!

Grouping &read across

Testing in REACH very last resort: (a.o. in art.13, 25 & in Annex XI)
8NT - ITS, Japan 09

When assessing hazards“Ideal Endpoint Coverage”

3 possible starting situations

OECD/GLP study
available

Performed:
nonOECD/GLP study

No test data

“Accepted by REACH”

Requirements met!

How to judge thisstudy?

No need for
additional NT data

Additional NT dataneeded?

Reliability OK;

9NT - ITS, Japan 09

Generate NT dataetc..
Sufficient?!

EBW ‘opties’:
Als geen NT data, dan is er ook geen
category-specific TTC afleidbaar….. envervallen we dus naar de heel lage
Munro of evt. Cramer TTC…

10

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The current situation on available testing data
for about 30.000 (?!) REACH chemicals > 1 tpa

141
Priority
Substances
2767 HPVCs>1000 tpa

• 14 %: base set data
• 65%: less than base set• 21%: no data

~ 27.000 other REACH substances>1 tpa(> 100.000 EINECS substances)
Allanou, Hansen and van Der Bilt, 1999
11

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data ?

The current situation on available testing data
for about 30.000 (?!) REACH chemicals > 1 tpa

141
Priority
Substances
2767 HPVCs>1000 tpa

• 14 %: base set data
• 65%: less than base set• 21%: no data

~ 27.000 other REACH substances>1 tpa(> 100.000 EINECS substances)
Allanou, Hansen and van Der Bilt, 1999
12

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data ?

Potential Impact of NT data
HPV Challenge Program (US.EPA, 2004)

Endpoint data sources

88% of the missing data wasfilled using read-across13

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Expected savings of NT in ITS under REACH

Van der Jagt et al., 2004
 Testing costs:€ 800-1130 million
 Number of animals: 1.3-1.9 million

EUR report, 2005 (http://ecb.jrc.it) Testing costs:€ 1.500 million
 Number of animals: 2.6 million

14

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Estimated test animal need under REACH(van der Jagt et al., 2004)
Test animal need for different endpoints(% of total test animals needed)
Two-generation reprotox
Developm. tox study
Further mutagenicity
Skin sensitisation
Long-term fish tox
Developm. tox screening
Accumulation
Short-term repeated dose
Carcinogenicity
Sub-chronic tox
Long-term repeated tox
Short-term fish
Acute inhalation tox
Acute dermal tox
Acute oral tox
In vivo eye irritation
In vivo skin irritation
Long-term bird
0

5

10

15

20

%

15

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25

30

35

40

2. Existing Guidance & Tools for generating NT data

16

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17

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Definitions

Structure Activity Relationship (SAR)a qualitative relationship that relates a (sub)structure to the presence or absence ofa property or activity of interest

Quantitative Structure Activity Relationship (QSAR)
a mathematical model relating one or more quantitative parameters derived fromchemical structure to a quantitative measure of a property or activity of interest

18

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Definitions (2)category approach & analogue approachdescribe techniques for grouping chemicals

read-acrossa technique of filling data gaps in either approach

19

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Definitions (3)chemical categorya group of chemicals whose properties
i.e. phys-chem, human health and/or environmental toxicological and/or environmental fateare likely to be similar or follow a regular pattern
as a result of structural similarity

In principle, the number of members generally present enables the detection of trends
across endpoints(and robustness of conclusions)20

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Definitions (4)analogue approacha limited number of chemicals whose properties
i.e. phys-chem, human health and/or environmental toxicological and/or environmental fateare likely to be similar
as a result of structural similarity

In principle, the limited number of chemicals do not allow identification of trends in theseproperties

21

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Step 1:Create a category

Category approach
CSA steps
1. Gather and share available information

Step 2:Gather data foreach member

2. Consider information needs
3. Identify information gaps
4. Generate new data / propose testing strategy

Step 3:
Evaluate adequacydata

Add or delete
members

Step 4:
Construct memberdata matrix

Not adequate
Fill gap by testing

Not adequate
Step 5:
Asses adequacy
and fill gap
Adequate
Step 6:
Document approach22

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Step 1:Category approach

Create a category

Is one available?
(US.EPA / OECD)Yes

Go to Step 5No

Create one withsimilarity tool(s)(e.g. ChemIDPlusAdvanced,
AIM, SciFinder, a.o.)Refine category by expert
judgement & alert tools(DEREK, TOPKAT,MCASE
a.o.)

23

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Step 5:
Asses adequacy
and fill gap

Go to Step 2
Step 2:Gather data foreach member

Step 4:
Construct memberdata matrix

Step 5:
Asses adequacy
and fill gap

Similar effects / observable trend

Member 1
Endpoint 1

Member X

Member 3

Endpoint n..
…………

24

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……….
……….

………..

……….
……….

……….
……….

……….

……….

Endpoint 2
Endpoint X

Member n..

!?
……….

……….
……….

How identify category members or analogues in Step 1?

ChemID (Plus Advanced)
AIM
SciFinder
OECD QSAR Toolbox
DSSToxa.o.

25

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How identify category members or analogues in Step 1?

By applying similarity principles:• common functional group(s) related to a specific activity (e.g. aldehyde,
epoxide, ester, specific metal ion)
• the likelihood of common precursors and/or breakdown products• an incremental and constant change across the category (e.g. a chainlength category with differences in methylene groups)• common constituents or chemical classes, similar carbon range numbers(UVCB substances)26

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ChemID(Plus Advanced)

?

?

27

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Read across: qualitative and quantitative

Qualitative: categorial similar responses (mut, sens, irrit..)

Quantitative: finding surrogate ‘DNEL’

28

NT - ITS, Japan 09→ next slideQuantitative read across:
DNEL

target22.2 mg/m3

source22.1 mg/m3

14.8 mg/m3

29

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Quantitative read across:
DNEL

target11.0 mg/m3

Based on AF of 2 for read across45.1 mg/m3

Based on own testing data

22.2 mg/m3

source22.1 mg/m3

14.8 mg/m3

30

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Organization for Economic Co-operation and Development“QSAR Application Toolbox”-filling data gaps using available NT data-

31

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What is the key feature of the Toolbox ?
to systematically group chemicals according to the presence or modulation ofa particular effect for all members of the category based on the presumptionof a common chemical or toxicological mechanism or mode of action.
to quickly evaluate all members of a category for common toxicologicalbehaviour or consistent trends among important regulatory endpoint data.

32

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What tools are in the Toolbox ?
The Toolbox estimates missing values by:
Read-Across,that extrapolates for an untested chemical from tested
chemicals within a category

Trend Analysis, that estimates for an untested chemical from a "trend"(increasing, decreasing or constant) in effect within a category(Q)SAR Models that estimate missing values from a statistical model for acategory33

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Structure of the QSAR Toolbox

Logical sequence of components usage
Chemical Profiling Endpoints Category
Filling Report
Logical sequenceof components
input
Definition
datausagegap

Use of components via:
 “rigid tract”
 “flexible tract”
34

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3. Our experience
On identifying similar structures

35•

All tools appear to have different similarity algorithms•

Basis of similarity algorithms is obscure (for toxicologists)•

Similarity outcome appears not always toxicologically-funded•

Additional expert judgement is needed

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Logical sequence of components usage

3. Our experience
OECD QSAR Toolbox• User friendly (once familiar to its structure)• Data very well organised• Toxicological and chemistry expertise is required• Reliability depends
on structure
data availability
Logicalsequencecomplexity,of components
usageand experience user
• Transparency high (reporting module)• At present limited to human health endpoints mutagenicity &sensitisation only36

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3. Our experience
Using NT data•

One should start with concrete cases and apply available
tools; to built capacity & expertise•

It is not be learned, like from a cookbook•

Toxicological and chemistry expertise needed (or hired)

Logical sequence of components usage

How will ECHA respond, what will it accept??

37

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4. Developments for generating NT data38

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The current situation on available testing data
for about 30.000 (?!) REACH chemicals > 1 tpa

141
Priority
Substances
2767 HPVCs>1000 tpa

• 14 %: base set data
• 65%: less than base set• 21%: no data

~ 27.000 other REACH substances>1 tpa(> 100.000 EINECS substances)
Allanou, Hansen and van Der Bilt, 1999
39

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data ?

The current situation on available testing data

Non-Testing data need Testing data!!
Existing data should be made (publicly) available!

New data should be generated in an intelligent way!

40

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Existing data should be made (publicly) available!
One initiative next to
Toxicology XML standard ( ToxML)
and Aggregated Computational Toxicology Resource (ACToR)

41

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DSSTox databases: Concept42

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DSSTox databases
Database

entries

DCPDB AS1481
DBP CAN209
DSSToxcurrently with 9 databases
EPA FHM617
operational
and accessable1217
by internet for
FDA DD
HPV CSI
3548
identifying
and
IRIS SI structural analogues
544
NCTR
ER
232
retrieving
associatedtoxicological
profilesNTP BSI
2415
NTP HTS
1408

43

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New data should be generated in an intelligent way!

Strategy to efficiently fill‘inadequately filled’ and ‘empty’
chemical categories(chemical domains)!!

44

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Once a datagap is ‘filled’ with NT data….

is that information sufficient to replace Testing data??
or
How to ‘weight’ NT dataandHow to ‘add’ NT data to Testing data…?

By Expert judgement or …… more formalized WoE…?
45

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Add different types of information in an ITS

46

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5. Exposure-based Waiving (EBW)47

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General rules for adaptation of Standard Requirements
Annex XI

1. Testing does not appear scientifically necessary
•
•
•
•
•

Use of existing data: PC, non-GLP etc, Historical human data
Weight of evidence
In vitro methods
Quantitative or Qualitative Structure Activity Relationships ((Q)SAR)
Grouping of substances and read-across approach

2. Testing is technically not possible
3. Substance-tailored exposure-driven testing48

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ITS: Information Gathering Strategy
Human data

Step 1: Gather all available Testing and Non-Testing information(Q)SAR
If not sufficient(for C&L and RA)

In vitro(Is Testing technically possible?)

Step 2: Is Exposure-Based Waiving an option?
If not possible

Exposure

Step 3: Perform / Propose Testing as last resort!!

Grouping &read across49

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EBW: General rules Annex XI
Tonnage

Health Information
requirements

1 – 10 tpa

•
•
•
•

In vitro skin and eye irritation
Skin sensitization
In vitro mutagenicity
Acute toxicity (one route)

10 – 100 tpa

•
•
•
•
•

In vivo skin and eye irritation
Further in vitro mutagenicity
Acute toxicity (2nd route)Sub acute toxicity (28d)
Reproductive toxicity screen

100 – 1000 tpa>1000 tpa

• Further mutagenicity tests• Sub-chronic toxicity (90d)*• Reproductive toxicity tests• Further mutagenicity tests• Chronic toxicity (>12 m)* may• Further reproductive toxicity
tests• Carcinogenicity may•*Sub acute toxicity (28d) is available
50

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Tests may be omitted based on
the exposure scenarios developed.
In all cases, adequate justificationand documentation shall be
provided of the exposure estimate
derived.

EBW: Specific rules
Tonnage

Health Information
requirements

1 – 10 tpa

•
•
•
•

In vitro skin and eye irritation
Skin sensitization
In vitro mutagenicity
Acute toxicity (one route)• None10 – 100 tpa

•
•
•
•
•

In vivo skin and eye irritation
Further in vitro mutagenicity
Acute toxicity (2nd route)Sub acute toxicity (28d)
Reproductive toxicity screen

•
•
•
•
•

100 – 1000 tpa• Further mutagenicity tests• Sub-chronic toxicity (90d) *• Reproductive toxicity tests>1000 tpa

• Further mutagenicity tests• Chronic toxicity (>12 m)* may• Further reproductive toxicity
tests• Carcinogenicity may•*Sub acute toxicity (28d) is available
51

Specific rules of adaptation ‘on exposure’(column 2 of Annexes VIII-X)

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NoNA
No (route specifics)
Relevant human exposure can be excluded...cf Annex XI.3
Relevant human exposure can be excluded...cf Annex XI.3

• NA
• unreactive, insoluble, and not inhalable, and no evidence ofabsorption & toxicity, coupled with limited human exposure.
• ….low tox, and no systemic absorption, and no or no
significant human exposure.
• NA• ….low tox, and no systemic absorption, and no or no
significant human exposure.
• NAGuidance?
Presently under construction:

Qualitative approach & Quantitative approach
Document by RIVM

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EBW, qualitative approach
Situations for EBW

Explanation

Specific use or limited emissions Certain uses excluded: - no consumer exposure- no professional application
Emissions to certain env compartments are excluded (e.g. air emissions
irrelevant as substance is solid and forms no dust).

53

Specific operational or use
conditions

Use in (semi)closed systems, leading to limited or negligible exposure
Use in strictly controlled systems with extensive PPE due to the toxicityof the substanceIntensity of use (duration,
frequency)

Infrequent use due to function of substance, e.g. specialty products forhighly specific occupational situations with a low frequency and duration

Substance properties

Phys-chem properties of preparation or article, e.g. when substance islocked in or covalently bound to matrix

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EBW, quantitative approach
When a qualitative justification is not preferred, not possible or notallowed:A quantitative approach cf Annex XI can be submitted:
adequate justification and documentation of waiving, based on an
exposure assessment cf Annex I.5: description of development of
an ES, and of the exposure estimation
This exposure estimate will be compared with a ‘DNEL’ or if this is
not available it may be possible to use a TTC (Threshold of
Toxicological Concern).
If this is not possible: additional hazard data need to be collected.

54

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EBW, quantitative approach
If ‘DNEL’ or TTC available:
Risk Characterisation Ratio (RCR)RCR =Exposure estimate of ES
‘DNEL’ or TTC

is determined

If RCR ≤ 1, then ‘control of risk’;document and communicate in CSR and SDS+
If RCR > 1, then ‘no control of risk’assessment needs to be refined55

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REACH & TTC values
present situation
route

workers

Based on route-specificdatabase for foodchemicals

consumers

man-v-env

TTC

?

?

?

?

?

?

?

oral
mg/kg bw,day

inhalation
mg/m3

dermalmg/kg bw,day; mg/cm2

56

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REACH & ‘DNEL’ values
present situation
route

workers

consumers

oral?
‘DNEL’

mg/kg bw,day

inhalation

man-v-env

?

?

?

?

?

?

mg/m3

dermalmg/kg bw,day; mg/cm2

i.e. = ‘chemical
category specific TTC’57

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What is ‘significant’ or ‘relevant’ exposure ?
DNELtarget11.0 mg/m3

Based on AF of 2 for read across45.1 mg/m3

Based on own testing data

22.2 mg/m3

source22.1 mg/m3

14.8 mg/m3

58

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If RWC exposure
estimates for ES would
give:
1 or 5 mg/m3…..

REACH & TTC values
present situation
TTC for oral route:- large database available (some identified exceptions)- but coverage REACH substances domain unclear
TTC for inhalation and dermal routes urgently needed:
Preferably route-specific, but:
- number of useful studies limited, and consequently- applicability to REACH substances domain limited
If obtained via appropriate route-to-route extrapolation:- larger database, higher coverage REACH substances domain,- but uncertainty on potential local effects
There is a need for tools to derive chemical category confined TTCs
59

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EBW: promising…….?
Guidance on Qualitative approach & Quantitative approach
under construction ….
3 EU SC developed an Opinion Document on TTC.. quite
critical on this tool…
CIE recently published revised legal section 3 Annex XI:
more stringent criteria…

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5. Final Conclusions
Additional chemistry & toxicological expertise clearly is needed to generate
and assess NT data.
The NT data area is a rapidly developing field: many new tools and options(note potential overlap when using more than one)The QSAR Toolbox is helpful and user-friendly tool but critically dependent
on more testdata input: DSSTox, ToxCast, Fraunhofer and a Japanesedatabases on complex human endpoints will be incorporated
EBW appears to become a difficult route……

61

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5. Final Conclusions (2)There are no worked-out examples
How will ECHA respond to any NT approaches?
Will REACH be achievable, then a ‘mind-set’ is needed!

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Thank you for your attention!

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