THRESHOLD OF TOXICOLOGICAL CONCERN (TTC); A STRATEGY … · THRESHOLD OF TOXICOLOGICAL CONCERN...
Transcript of THRESHOLD OF TOXICOLOGICAL CONCERN (TTC); A STRATEGY … · THRESHOLD OF TOXICOLOGICAL CONCERN...
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.