ttc basics and latest developments - ilsi...

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TTC – BASICS AND LATEST

DEVELOPMENTS

Non-oral Routes and Influence of Local

Effects

Continuing Education Course - Eurotox 2015 Porto

Sylvia Escher, Fraunhofer ITEM

© Fraunhofer

Dr. Sylvia Escher

Chemical Risk Assessment

Databases and Expert systems

Fraunhofer Institut für Toxikologie und experimentelle Medizin,

Hannover

Non-oral Routes and Influence of Local

Effects

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Toxicology

Testing (focus on inhalation)

Fraunhofer ITEM -Overview

Pre-clinical

Pharmacology

Early-Phase

Clinical Trials

Manufacturing of

Biopharmaceuticals

for Clinical Trials

Environmental,

Occupational and

Consumer Protection

Registration and

Risk Assessment

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Cramer et al. grouped chemicals into 3 structural classes

via a series of 33 questions:

I = low, II = medium, III = high toxicity

Thresholds based on RDT studies with oral exposure

Current TTC concept

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Human exposure

Beside oral exposure humans are exposed to chemicals via

inhalation or dermal uptake

• Is the TTC concept applicable to these other routes of

exposure?

• Under which conditions?

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TTC dermal uptake

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TTC dermal uptake (1)

TTC use for cosmetic ingredients (COLIPA proposal)*

The COLIPA Expert Group concluded that it is scientifically justifiable to use the

TTC approach and the database underlying the TTC values established for food

chemicals for the safety evaluation of cosmetic ingredients and impurities.

• Applicability domain: Chemical structures of cosmetic ingredients and cmpds in

the TTC databases comparable (Kroes et al. 2007)

• Exclude chemicals that have or are suspected to have pharmacological

properties (Kroes et al. 2007)

• TTC approach not applicable to assess local effects. In principle possible, but

the databases on local effects (e.g. skin irritation and contact allergies) are

currently too small.

• Systemic exposure after topical application to be measured or estimated e.g. by

using Jmax (maximum flux).

* SCCP/1171/082012: Opinion on the Use of the TTC Approach for Human Safety Assessment of

Chemical Substances with focus on Cosmetics and Consumer Products

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Differences in systemic bioavailability - route-dependent differences after topical

exposure compared to oral uptake

• More extensive first pass metabolism in the liver, compared with the skin, prior to

reaching the general circulation.

• Slower and incomplete transfer across the skin compared with the intestinal wall,

due to the physico-chemical properties of the chemical and different

physiological properties of the tissues.

• The 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.

TTC values for Cramer Class I-III cmpds likely to overestimate the potential toxicity

of the same chemical following topical exposure, even if 100% of the topical dose

entered the systemic circulation. (Kroes et al., 2007).

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* Kroes et al. (2007) Application of the threshold of toxicological concern (TTC) to the

saftey evaluation of cosmetic ingredients. Food and Chem Toxicol 45, 2533-2562

Jmax (µg/cm2/h) Default % dose

absorbed per 24 h

Non-reactive cmpd with MW > 1000

Da

Negligible

Jmax <0.1 10

0.1 >Jmax <10 40

Jmax > 10 80

Proposed default adjustment factors for the % absorbed dose of cosmetic

ingredients across the skin *

Not covered rinse of products such as shampoos with short exposure period

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TTC inhalation exposure

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TTC inhalation exposure (1)

• Screening tool for assessment of air contaminants (Drew and

Frangos, 2007).

• General ToR of 1.5 μg/person/d from FDA used to calculate a

"Concentration of No Toxicological Concern" (CoNTC).

• 50% of the ToR, human body weight of 70 kg, inhalation of 20 m3 of

air per day a general TTC for air contaminants calculated as 0.03

μg/m3.

• CoNTC compared with occupational exposure limits (OEL): OELs

divided by a factor of 42

• factor of 4.2 to convert occupational (8h/d; 5d/w) to consumer

exposure (24 h/d; 7 d/w)

• factor of 10 to account for greater intraspecies sensitivity of the

general population as compared to workers

• 4/1857 OEL values (0.2%) below the CoNTC

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TTC inhalation exposure (2)

Is it possible to use the Cramer decision tree to determine inhalation

thresholds?

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TTC inhalation (2): Application of Cramer

decision tree to inhalation datasets

• TTC inhalation < orale TTC

• Route specific difference?

Dataset Route Type N Class 1 Class 3

Munro et al. 1996 Oral General 611 1800 90

Carthew et al.

2009

Inhalation Local 92 200 67

Systemic 92 980 170

RepDose

(Escher et al.

2010)

Inhalation General 203

(136*)

71

(180*)

4

(4*)

* Cmpds with structural alert for genotoxicity excluded

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Local versus systemic effects

Hypothesis*

Sensitivity to local effects differs for

inhalation and oral exposure

To be confirmed:

Are targets of the resp. tract more

frequently affected than other targets?

Do effects in the respiratory tract occur at

LOEL? Are these effects more sensitive?

*Escher et al. 2010

wikipedia

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Frequency of targets at LOEL in inhalation studies

Local targets frequently occur at the LOEC of inhalation studies

Escher et al. 2010

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Inhalation TTCs

• New grouping concept developed

• large database on RDT studies with inhalation exposure

• Dataset splitted into high toxic, moderate toxic and low toxic cmpds

based on NOEC distribution

• 21 structural groups identified being charateristic for high or low

toxicity

• MoA analysis, PC properties, structural homogenity to conclude on

final grouping (28 structural groups)

• TTC values derived for groups of toxic and lower toxic cmpds

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TTC database

www.repdose-fraunhofer.de

29%

66%

4% 1%

Routes inhalation oral dermal other

TTC dataset

608 inhalation studies

296 cmpds

834 inhalation studies/

362 cmpds

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Characterisation of TTC dataset

Local versus systemic effects at LOEC

„Local effect“

N= 56 cmpds

„systemic effect“

N=148 cmpds

„Local and systemic effects“

N=62 cmpds

„Local DB“

N= 118 cmpds

„systemic DB“

N= 210 cmpds

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Inhalation TTCs

• Results submitted for publication

1. Inhalation Threshold of Toxicological Concern (TTC) - Structural

Alerts Discriminate High from Low Repeated-Dose Inhalation

Toxicity. G. Schüürmann, R.U. Ebert, I. Tluczkiewicz, S.E. Escher,

R. Kühne. Environment International, submitted August 2015

2. Inhalation TTC values: A new integrative grouping approach based

on structural, toxicological and mechanistic features. I.

Tluczkiewicz, R. Kühne, R. U. Ebert, M. Batke, G. Schüürmann,

Inge Mangelsdorf, S.E. Escher. Regulatory Toxicology and

Pharmacology, submitted August 2015

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Route independent TTC values?

• Internal dose instead of external dose will enable route to route

extrapolation

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Route independent TTC values?

• Internal dose instead of external dose will enable route to route

extrapolation*

• Three independent datasets used

• Munro DB (Munro et al. 1996, N=613)

• New chemical database (ELINCS DB, N=765)

• Database on food contact materials (FCM DB, N=199)

• Oral external NOAELs were converted to internal NOAELs taking into

account bioavailability by using an in silico prediction tool (ACD

Percepta from ACD Labs)

* Partosch et al. (2014) Internal threshold of toxicological concern values: enabling route to

route extrapolation. Arch Toxicol. DOI 10.1007/s00204-014-1287-6.

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Comparison: Internal TTC vs. external TTC



Cramer class TTC type Munro DB ELINCS DB FCM DB

N=137 N=53 N=97

Class 1 TTC extern 53.4 60 10

TTC intern 1 22.8 5.2

N=476 N=712 N=102

Class 2+3 TTC extern 2 24.8 3

TTC intern 0.15 0.07 0.0012

TTC given as µg/kg bw/d; based on the empiric 5th NOAEL percentile;

Default uncertainty factor of 100 used for external and 25 for internal TTC

values.

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Proposed internal TTC values



Internal TTC

Cramer class 1

Internal TTC

Cramer class 2+3

Based on 5th NOAEL 6.9 0.1

90% Confidence

interval

3.8-11.5 0.08-0.14

© Fraunhofer

Dr. Sylvia Escher

Chemikalienbewertung

[email protected]

Fraunhofer-Institute für Toxikologie und Experimentelle Medizin

Nikolai-Fuchs-Straße 1

30625 Hannover

Tel: +49 (0) 5 11 / 53 50 - 330

Fax: +49 (0) 5 11 / 53 50 - 335

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