THRESHOLD OF TOXICOLOGICAL CONCERN (TTC); A STRATEGY TO

SUPPORT APPLICATION OF TTC TO DERMALLY APPLIED COSMETIC

INGREDIENTS

Threshold of Toxicological Concern (TTC) is a

tool that aids assessment of human health

risks from exposure to low levels of chemicals

in the diet, when specific toxicity data are not

available. It provides threshold toxicity values

for oral dosing in structural categories (Cramer

classes 1, 2 and 3 (1800, 540 and 90

ug/day1.8, 2 0.54 and 3 0.09 mg/d ).

Our aim is to adapt the TTC concept to

cosmetics applied to the skin and address the

importance of differences in bioavailability

between oral and dermal exposures.This

poster describes a decision tree approach for

estimating systemic availibility following dermal

exposure, allowing application of oral TTC.

….

Objectives • An eleven step decision tree (figure 1) has been developed based

on estimated usage/skin exposure, dermal absorption derived

from the J max prediction, J max adjusted or experimental

absorption data to estimate systemic dose for ranking against

TTC value. Jmax (maximum flux) was derived from Potts and

Guy equation.

• Data are obtained from a new dermal absorption database with

cosmetics-related chemicals www.cosmostox.eu

• The decision tree was evaluated with exposure scenarios for five

cosmetic molecules (methylisothiazolinone, diethylphthalate,

resorcinol, butyl paraben and quercetin and the contaminant

dioxane.(table1 abbreviated version shown ).

• Both skin exposure (100% default absorption) or Jmax (maximum

flux from saturated aqueous solution) have over estimated

systemic dose which exceeded oral TTC value. Using flux

corrected for in use exposure, realistic systemic availability gave

values close to TTC.

• Oral to dermal bioavailability differences may be important for example in hydrolysis of the ester butyl paraben.

Approaches

Faith. M. Williams1, A. Chiodini, G. Barrett3, M. Cronin4, R. H. Guy5, J. Plautz6, N.A. Montiero-Riviere7,

C. Roper8, H. Rothe9, D. Rua10J. Westerhout, C. Yang12

1 Newcastle University, Newcastle upon Tyne, NE2 4AA, UK, 2 ILSI Europe, 1200 Brussels, BE,3 Health Canada, Ottawa – Ontario, CA, 4 Liverpool John Moores University, Liverpool, L3 3AF, UK,5 University of Bath Bath,

BA2 7AY, UK,6 DSM Nutritional Products, 4002 Basel, CH, 7Kansas State University, Manhattan, KS 6650-5802,US 8Charles River Laboratories, Edinburgh, EH33 2NE, UK, 9 The Procter & Gamble Company, 64274

Darmstad, DE, 10US FDA 20740 USA, 11TNO, 3700 AJ, Zeist, NL, 12Altamira LLC, Columbus, OH 43235, USA.

Figure 1 Decision tree

Table 1 Decision tree evaluation

Funding from ILSI-EU and EU (FP7/2007-

2013) COSMOS Project grant agreement n° 266835

Conclusions Threshold of Toxicological Concern (TTC)can be applied to dermally

applied cosmetic chemicals using a decision tree to estimate systemic

availability.

Predictions aid estimation of systemic availability where dermal

absorption data under in-use scenarios is limited.

Rules for oral to dermal bioavailability extrapolation will be included

where differences exist for example in local metabolism.