Shi, Q;
Carrillo, JC;
Penman, MG;
Manton, J;
Fioravanzo, E;
Powrie, RH;
Elcombe, CR;
... Boogaard, PJ; + view all
(2022)
Assessment of the Intestinal Absorption of Higher Olefins by the Everted Gut Sac Model in Combination with in Silico New Approach Methodologies.
Chemical Research in Toxicology
, 35
(8)
pp. 1383-1392.
10.1021/acs.chemrestox.2c00089.
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Abstract
To reduce the number of animals and studies needed to fulfill the information requirements as required by Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (EC no. 1907/2006), a read-across approach was used to support approximately 30 higher olefins. This study aimed to assess the absorption potential of higher olefins through the gut wall as the experimentally determined bioavailability which would strengthen the read-across hypothesis and justification, reducing the need for toxicity studies on all of the higher olefins. The absorption potential of a series of higher olefins (carbon range from 6 to 28, with five configurations of the double bond) was determined in the in vitro everted rat small intestinal sac model and subsequently ranked. In addition, in silico approaches were applied to predict the reactivity, lipophilicity, and permeability of higher olefins. In the in vitro model, everted sacs were incubated in "fed-state simulated small intestinal fluid" saturated with individual higher olefins. The sac contents were then collected, extracted, and analyzed for olefin content using gas chromatography with a flame ionization detector. The C6 to C10 molecules were readily absorbed into the intestinal sacs. Marked inter-compound differences were observed, with the amount of absorption generally decreasing with the increase in carbon number. Higher olefins with ≥C14 carbons were either not absorbed or very poorly absorbed. In the reactivity simulation study, the reactivity is well described by the position of the double bond rather than the number of carbon atoms. In the lipophilicity and permeability analysis, both parameter descriptors depend mainly on the number of carbon atoms and less on the position of the double bond. In conclusion, these new approach methodologies provide supporting information on any trends or breakpoints in intestinal uptake and a hazard matrix based on carbon number and position of the double bond. This matrix will further assist in the selection of substances for inclusion in the mammalian toxicity testing programme.
| Type: | Article |
|---|---|
| Title: | Assessment of the Intestinal Absorption of Higher Olefins by the Everted Gut Sac Model in Combination with in Silico New Approach Methodologies |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.chemrestox.2c00089 |
| Publisher version: | https://doi.org/10.1021/acs.chemrestox.2c00089 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Keywords: | Alkenes, Animals, Carbon, Intestinal Absorption, Intestine, Small, Mammals, Permeability, Rats |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10164140 |
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