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

Health and Consumers

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