The European Commission non-food Scientific Committees Scientific Committee on consumer safety - SCCS

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1 The European Commission non-food Scientific Committees Scientific Committee on consumer safety - SCCS Health and Consumers

2 Threshold of toxicological concern (TTC) Cosmetics a special case? Thomas Platzek, Berlin Health and Consumers

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 Procedure Knowledge of structure and exposure Classification into a toxicity class (Cramer) following a decision tree and definition of a TTC value Class TTC µg/person/day TTC µg/kg bw/d Genotoxicity alert Organophosphate, Carbamate Cramer Class III Cramer Class II Cramer Class I Kroes et al T. Platzek, TTC Brussels 2014 Page 3

4 EFSA flow chart Is the substance a member of an exclusion category? * Yes Substance not expected to be of safety concern ** No No No Is there a structural alert for genotoxicity (including metabolites)? No Exposure > 0.3 µg/kg bw/day? *** Is substance an OP/Carbamate? No Yes Yes Exposure > 1.5 µg/kg bw/day? *** Exposure > µg/kg bw/day? No Low probability of safety concern ** Yes Yes Substance requires non-ttc approach (toxicity data, read-across etc.) No Yes Is substance in Cramer Class II or III? No Exposure > 30 µg/kg bw/day? *** Yes Yes * Exclusion categories high potency carcinogens; inorganic substances; metals; proteins; steroids; substances known/predicted to bioaccumulate; insoluble nanomaterials; radioactive substances. ** If exposure of infants < 6 months is in range of TTC consider if TTC is applicable *** If exposure only short duration consider margin between human exposure & TTC value T. Platzek, TTC Brussels 2014 Page 4

5 TTC database (Munro et al 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 Databases 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

6 Database of carcinogenic substances CPDB carcinogenic potency database (Gold et al ff) Contains now 730 carcinogenic substances Linear extrapolation from TD 50 value to a virtual safe dose (VSD) (dose exhibiting 1 x 10-6 risk) Kroes et al ppb in diet = 1.5 µg / person = 25 ng/kg bw 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)

7 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 10 6 ), 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.

8 Application of TTC in cosmetics Kroes et al 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.

9 Default adjustment factors for percutaneous absorption Prediction of percutaneous absorption Log K p = x log P x MW (correction for lipophilic compounds ) K P = permeability coefficient (cm/h) P = octanol water partition coefficient MW = molecular weight J max = K P (corrected) x C (saturation, in water) J max 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/cm 2 /h) MW (Da) logp Category Jmax = 0 > 1000 Da Any Negligible Jmax < 0.1 > 300 < 1 or > 5 Low 0.1 < Jmax < > 2.0, 2.5 Medium low 1.0 < Jmax < Medium high 10 < Jmax < High Jmax > 100 < High

10 Default adjustment factors for percutaneous absorption Proposed default adjustment factors for the % dose absorbed of cosmetic ingredients across the skin Jmax (µg/cm 2 /h) MW > 1000 Default % dose absorbed per 24 h Negligible Jmax < < Jmax < Jmax > 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

11 Assessment by SCCS/SCHER/SCENIHR 1. TTC database and cosmetic ingredients a) Munro database 613 substances vs COSING database CAS RNs and 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).

12 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.

13 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).

14 Assessment by SCCS/SCHER/SCENIHR 4. TTC for chemicals with genotoxicity alert TTC approach: - reference point TD 50 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 TD 50 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.

15 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.

16 Conclusion Regulatory toxicologists in Europe have been discussing the TTC approach since more than a decade, e.g. the previous SCF 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.

17 Conclusion 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.

18 THANK YOU Health and Consumers