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2015-07-03
1
2015-07-01 SCCS WG on methodologies 1
Potency classification of skin sensitizers
(EC WG on Sensitization)
Carola Lidén, Professor, MD
Carola Lidén
Occupational and environmental dermatology
Clinical, experimental and epidemiological research
Risk assessment tasks
− SCCP member (2004-2009); SCCS external expert (2009-2012)
− OECD Test Guideline: skin sensitization (1992)
− EC WG sensitization: potency (2002-2003)
− OECD WG sensitization: GHS classification (2003-2008)
− ECHA CLP: guidance on application of the CLP criteria (2012-2013)
Funding
- Karolinska Institutet and Stockholm County Council
- Swedish Research Council for Health, Working Life and Welfare
2015-07-01 SCCS WG on methodologies Carola Lidén 2
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2015-07-01 SCCS WG on methodologies 3 Carola Lidén
The clinical disease: allergic contact dermatitis
Clinical tests
Diagnostic
patch test
Baseline
series
Special series,
serial dilutions Repeated open
application (ROAT)
Species Induction /
sensitization
Elicitation / allergic reaction /
disease
Human Skin exposure
(products, mixtures,
articles, etc)
Disease:
− allergic contact dermatitis
Clinical tests:
− diagnostic patch test
− dose-response (ROAT etc)
Guinea pig GPMT, Buehler (subst) Challenge testing
Mouse LLNA (subst) -
Human HRIPT etc Challenge testing (not clinical tests)
2015-07-01 SCCS WG on methodologies Carola Lidén 4
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2015-07-01 SCCS WG on methodologies 5 Carola Lidén
Guinea pig: GPMT, Buehler
Mouse: LLNA
WG sensitization 2002-2003
TC on classification and labelling,
harmonized classification
First question:
Propose how to use the existing
methods in order to grade allergen
potency, providing detailed guidance
for current predictive test methods
The approach has been introduced
in GHS and CLP
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Potency categorization of classified skin sensitizers
based on LLNA
EC3 value
(%)
EC WG sens
& SCCP
CLP & GHS
(H317 former
R43)
EC3 value
(%) ECETOC
≤0.2 extreme 1A <0.1 extreme
>0.2 - ≤2 strong 1A ≥0.1 - <1 strong
>2 moderate 1B ≥1 - <10 moderate
≥10 - ≤100 weak
2015-07-01 SCCS WG on methodologies Carola Lidén 7
EC3 value: the amount of a chemical that is required to elicit a three-fold
increase in lymph node cell proliferative activity (SI ≥ 3)
Basketter et al 2005; SCCP 2005; Guidance on the Application of the CLP Criteria ver 4 2013;
GHS 5th rev 2013; ECETOC 2003
Potency categorization based on GPMT or Buehler Test
Categorization is based on
- intradermal induction concentration in the GPMT
- topical induction concentration in the Buehler test
Methods designed for assessment of sensitization potential (yes or no),
not potency
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How to deal with discrepancies
When EC3 values are available from more than 1 study, the
lowest value should normally be used
Where multiple animal data sets lead to different categorization of
the same substance, the higher potency category should apply
Human data may indicate the need to change the potency
categorization derived from animal experiments. Normally, only
for re-categorization into a higher potency category
2015-07-01 SCCS WG on methodologies Carola Lidén 9
Basketter et al 2005
Submissions to SCCP often insufficient
LLNA
- Conc: too low, too high, too narrow span
- Vehicle: inadequate, not prio
GPMT
- Conc: too low for induction, challenge
- Often no dose-range-finding test
SCCP conclusions often inconsistent
SCCP memorandum
- OECD TG requirements
- Potency categories
2015-07-01 SCCS WG on methodologies Carola Lidén 10
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Memorandum on hair dye substances and their skin
sensitising properties. SCCP 19 December 2006
Memorandum on hair dye chemical sensitisation.
SCCS 26 February 2013
Opinion on fragrance allergens in cosmetic products.
SCCS 26-27 June 2012
Other SCCP and SCCS opinions
2015-07-01 SCCS WG on methodologies Carola Lidén 11
Yazar et al, manuskript
Skin
sensitizing
potency
according to
LLNA (EC3)
2015-07-01 SCCS WG on methodologies Carola Lidén 12
2.0
0.2 Cinnamal
HICC
Citronellol
Formald
MDBGN
MCI/MI
MI
BIT
Imidurea
PPD
TDA
npPPD
2mRes
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2015-07-01 SCCS WG on methodologies 13 Carola Lidén
Conclusions
The categorization in the SCCP memorandum was recently
implemented in GHS and CLP
Animal tests will continue to be important for SCCS
- LLNA and GPMT. Modifications may give more information
Human data on elicitation
-Elicitation thresholds are much lower and correlate poorly with
induction potency
- Essential basis for prevention of clinical disease
2015-07-01 SCCS WG on methodologies Carola Lidén 14