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Health and Consumers
The European Commission non-food Scientific
Committees
Scientific Committee on consumer safety - SCCS
Health and Consumers
Threshold of toxicological concern (TTC)
Cosmetics – a special case?
Thomas Platzek, Berlin
T. Platzek, TTC Brussels 2014 Page 3
TTC Threshold of Toxicological Concern
Thesis Dependent on the structure, an exposure dose with low concern of systemic toxicity can be set for any substance even in the absence of substance specific toxicity data
Precondition Knowledge of structure and exposure
Procedure Classification into a toxicity class (Cramer) following a decision tree and definition of a TTC value
Kroes et al. 2004
Class TTC µg/person/day TTC µg/kg bw/d
Genotoxicity alert 0.15 0.0025
Organophosphate, Carbamate
18 0.3
Cramer Class III 90 1.5
Cramer Class II 540 9
Cramer Class I 1800 30
T. Platzek, TTC Brussels 2014 Page 4
EFSA flow chart
Is the substance a member of an
exclusion category? *
Is there a structural alert for
genotoxicity
(including metabolites)?
Exposure > 0.3 µg/kg bw/day? ***
Is substance an OP/Carbamate?
Exposure > 1.5 µg/kg bw/day? ***
Is substance in Cramer Class II or III?
Exposure
> 0.0025 µg/kg bw/day?
Substance
requires non-TTC approach
(toxicity data, read-across etc.)
Low probability of
safety concern
**
Substance not expected
to be of safety concern
**
Exposure > 30 µg/kg bw/day? ***
No
No
No
Yes
No
Yes
No
Yes
Yes
Yes
Yes
Yes
*** If exposure only short duration
→ consider margin between human
exposure & TTC value
** If exposure of infants < 6 months
is in range of TTC
→ consider if TTC is applicable
No
No
No
Yes
* Exclusion categories
high potency carcinogens; inorganic substances;
metals; proteins; steroids; substances
known/predicted to bioaccumulate; insoluble
nanomaterials; radioactive substances.
TTC database (Munro et al. 1990 ff)
• 613 substances, oral toxicity data
• chronic, subchronic, reproductive and developmental toxicity
• sources: NTP, JECFA, IRIS (integrated risk information system) EPA, DART (developmental and reproductive toxicology)
RepDose (Escher, Mangelsdorf 2009)
• ITEM Fraunhofer Institute ca. 600 industrial chemicals, subchronic and chronic toxicity
• TTC RepDose (Tluczkiewicz et al. 2011)
• Combined database
ELINCS (Kalkhoff et al. 2011)
• 861 new industrial notified chemicals, subacute and subchronic toxicity
FCM (Pinalli et al. 2011)
• Comparison of TDI/NOAEL of 845 FCM substances (232 in addition to Munro) with TTC: 96% of the TTCs was lower
Cosmetics COSMOS project COLIPA + EU Commission + ILSI
Databases
Database of carcinogenic substances
CPDB carcinogenic potency database (Gold et al. 1984 ff)
Contains now 730 carcinogenic substances
Linear extrapolation from TD50 value to a virtual safe dose (VSD)
(dose exhibiting 1 x 10-6 risk)
0.5 ppb in diet = 1.5 µg / person = 25 ng/kg bw
Kroes et al. 2004
• Exclusion of high potency classes (aflatoxin, N-nitroso, azoxy)
• Substances with structural alert for genotoxicity
TTC 0.15 µg / person = 2.5 ng/kg bw
Comment of the EU SCs
1. The CPDB contains a number substances for which the VSD is below 0.15
µg/person per day, and which do not fall within the three groups of high potency
carcinogens recommended for exclusion by Kroes et al. (2004).
2. Further work is necessary to strengthen the scientific basis for the TTC value of
0.15 µg/person per day for genotoxic carcinogens.
3. It was proposed to derive VSD only from recognized human carcinogens
(e.g. IARC classified 166 substances)
Some crucial points
Cramer classes
Cramer et al. (1978) based their decision tree on a series of 33 questions
relating mostly to chemical structure, and natural occurrence in food and in the
body were also taken into consideration. The logic of the sequential questions
was based on the then available knowledge on toxicity and on how chemical
structures are metabolised in mammalian metabolic pathways.
Toxtree software
Use of the Kroes et al. (2004) TTC decision tree results in three possible
outcomes: (a) not be expected to be a safety concern, (b) negligible risk (low
probability of a life-time cancer risk ˃1 in 106), and (c) risk assessment requires
compound-specific data. Toxtree incorporates the Benigni/Bossa rules for the
identification of some genotoxic carcinogens (Benigni et al. 2008), and requires
the user to input the estimated daily intake (exposure).
Chemoinformatic analysis
Chemical space analysis (structure, size, shape, reactivity) was performed to
analyse if Munro database is representative for world of chemicals.
Application of TTC in cosmetics
Kroes et al. 2007
• Consideration of:
1. Similarity between cosmetic ingredients and the Munro database
2. Route-dependent differences in first-pass metabolism dermal vs. oral
3. Default factors for percutaneous absorption
4. Estimation of aggregate internal exposure
• Conclusion of the authors
For many of the cosmetic ingredients groups TTC may be applicable.
► More extensive first pass metabolism in the liver, compared with the skin
► Slower and incomplete transfer across the skin compared with the intestinal
wall, due to different physiological properties
► Slower absorption after topical application may result in a different
shape of the plasma concentration–time curve, even if the area under the
curve is identical.
Default adjustment factors for percutaneous absorption
Prediction of percutaneous absorption
Log Kp = 2.7 + 0.71 x log P - 0.0061 x MW KP = permeability coefficient (cm/h)
P = octanol water partition coefficient
(correction for lipophilic compounds ) MW = molecular weight
Jmax = KP (corrected) x C (saturation, in water) Jmax maximum flux
Classification of chemicals (on the basis of their physicochemical properties) in terms of their potential to be absorbed across the skin
Jmax (µg/cm2/h) MW (Da) logP Category
Jmax = 0 > 1000 Da Any Negligible
Jmax < 0.1 > 300 < 1 or > 5 Low
0.1 < Jmax < 1.0 200–300 > 2.0, 2.5 Medium low
1.0 < Jmax < 10 150–250 1.0–2.0 Medium high
10 < Jmax < 100 60–200 0.5–3.5 High
Jmax > 100 <150 0.5–2.0 High
Default adjustment factors for percutaneous absorption
Proposed default adjustment factors for the % dose absorbed of cosmetic
ingredients across the skin
Jmax (µg/cm2/h) Default % dose absorbed per 24 h
MW > 1000 Negligible
Jmax < 0.1 10
0.1 < Jmax < 10 40
Jmax > 10 80
Default adjustment factors for rinse-off products
Skin contact < 1 h, default retention factors 1% (e.g. shower gel or 10% (e.g. hair
dyes)
Default adjustment factors for intermittent use
Time interval > 7 days
once per week factor 3
Less than once per week factor 10
Assessment by SCCS/SCHER/SCENIHR
1. TTC database and cosmetic ingredients
a) Munro database 613 substances vs COSING database
9 286 CAS RNs and 19 390 INCI names
b) Certain structural classes are missing (e.g. organometallics,
silicones, non-ionic and cationic surfactants).
c) Chemicals with complex structures are not adequately covered in
the Munro database. It is necessary to include toxicity data on these
compounds and other complex structures (e.g. UV-filters) into the
database to be used for derivation of TTCs for cosmetics.
d) Reality check: comparison of TTC-derived values with experimental
“TDIs” of cosmetic ingredients to check for misclassification.
e) Chemical space analysis is being performed, i.e. comparison of
intrinsic properties (size, shape) and derived properties (chemical
reactivity).
Assessment by SCCS/SCHER/SCENIHR
2. Exposure assessment a) Dermal absorption SCCS Notes of Guidance:
In case the results are derived from an inadequate in vitro study, 100% dermal absorption is used. In case MW > 500 Da and log Pow is smaller than -1 or higher than 4, the value of 10% dermal absorption is considered.
b) Comment of the SCs: The use of an adjustment factor for percutaneous absorption needs further elaboration based on a broad systematic comparison of predicted and experimentally obtained percutaneous absorption values
c) Comment of the SCCS to adjustment for intermittent exposure If exposure is only for a number of days per year, the exposure value is the actual dose on the exposure days, and not the daily dose averaged out (and thus divided!) over the whole year [EChA 2008b, exception genotoxic carcinogens!].
d) Default adjustment factors for rinse-off products The SCCS adjustment factors are used since 2003 and are generally accepted.
Assessment by SCCS/SCHER/SCENIHR
3. Route-to route extrapolation
MOS calculation according to Notes of Guidance SCCS:
MOS = NOAEL / SED
• NOAEL oral subchronic toxicity study
CAVE: oral absorption is rarely known, default 50%
• SED dermal absorption in vitro
determination of the amount systemically available
• In the case of orally poorly absorbed substances the MOS is not
conservative
• For cosmetic ingredients any risk assessment as well as the TTC
approach should be based on internal doses (internal TTC).
Assessment by SCCS/SCHER/SCENIHR
4. TTC for chemicals with genotoxicity alert
TTC approach: - reference point TD50 of the Gold database - linear extrapolation - exclusion of high potency classes
Criticism SCs: ► 4.1% of the substances in the Gold database have a cancer risk > 10-6 at the TTC 2.5 ng/kg bw/d ► For 1/3 of human carcinogens the TTC is not protective ► TD50 is not the adequate reference point for extrapolation ► No allometric scaling
Proposal SCs: ► Acceptance of the TTC value only preliminarily
► Reconsider the TTC value: The probability that exposure to an untested genotoxic carcinogen results in a cancer risk higher than 1 x 10-6 should be minimized.
- extending the database to cover all available studies - using allometric adjustment factors and/or using the T25 or 1, 5 or 10% benchmark dose as point of departure for linear extrapolation.
Assessment by SCCS/SCHER/SCENIHR
5. Further critical points
a) Dose descriptor
Comparison of toxicity of chemicals might be better addressed by expressing doses
(potencies) on a molar basis (mmol/kg bw/day).
Usually, TTC is expressed in dose per person per day.
The SCs advise to express TTC in dose per body weight per day
b) Infants
Give special consideration to infants under the age of 6 months because of the the
potentially immature metabolism for some chemicals structures, in particular when the
estimated exposure is in the range of the TTC value.
c) Classification
►Several recent analyses have revealed regular misclassification of compounds
when using the Cramer decision tree in its present form.
► The SCs accept in principle the division into Class I and Class III. For Class I,
classification should be carefully considered and justified. If classification in
Class I cannot be justified the SCs recommend using Cramer Class III.
► All scientific information available today should be used to define the various
toxicity classes before expanding the number of classes, i.e. the classification
scheme should be modified based on up-to-date toxicological knowledge and
recent developments e.g. QSAR.
Conclusion
Regulatory toxicologists in Europe have been discussing the TTC approach since more than a decade, e.g. the previous SCF 1996. Two European committees have discussed possible applications.
The EFSA Scientific Committee issued an opinion exploring options for the application in food and feed, e.g. for impurities of food additives, thermal reaction products, food contact materials, contaminants etc.
An EU non-food expert Committee consisting of members of SCCS, SCHER and SCHENIR discussed the TTC concept in general as well as additional possible fields of application with the focus on cosmetics.
Major aspects to be considered are applicability domain, route to route extrapolation and exposure assessment.
COSMOS project: comparison of TTC and experimentally derived „TDIs“, chemical space analysis, prediction of human repeated dose toxicity
For cosmetic ingredients the TTC approach should be based on internal doses.
Prediction of exposure to cosmetic ingredients should use a probabilistic procedure whenever possible and remains a challenge.
The TTC approach as presently proposed is in general acceptable.
It needs, however, further research and refinement with regard to Cramer
classification as well as for the TTC value for substances with genotoxicity alert.
The refinement of the TTC approach should take into account the up-to-date
toxicological knowledge including QSAR.
There is no distinction between toxicity induced either by intentionally added
ingredients or inadvertent contaminants. However, primary ingredients added to
products are often regulated, also certain cosmetic ingredients (e.g.
preservatives). A requirement for toxicity testing data is appropriate for such
substances.
With cosmetics specific problems may arise in praxi:
According to the new EU cosmetic legislation the safety of cosmetic products
available on the market has to be assessed by the manufacturer or importer.
Assessors in small enterprises with limited toxicological experience may apply the
TTC approach, e.g. by running the TOXTREE software.
Therefore, a cosmetic-specific decision tree has to be built to minimize misuse of
the approach.
Conclusion