Toxicology of Industrial Compounds

326 ANTIOXIDANTS AND LIGHT STABILISERS: TOXIC EFFECT
Table 23.5 Summary of pharmacokinetic parameters obtained after single oral
administration of 10 mg kg −1 Compound D and E to two male rats each
Notes:
a Below the limit of reliable quantification.
pe: Parent equivalent.
acid, Compound C, and unidentified metabolites, respectively, to the total
AUC. It is assumed that the majority of unidentified metabolites have
arisen from further biotransformation of the carboxylic acid. The
significant contribution of hydrolysis products to the total AUC is still
evident after 168 h although low blood radioactivity levels 24 h after
dosing generally prevented accurate quantitation of the metabolites and
thus slightly diminished their apparent overall share (Table 23.5).
Liver enzyme induction
Subchronic oral (gavage) administration of single daily doses of Compound
C for 14 days, Compound D for 14 days, Compound E for 13 weeks, and
Compound F for 114 days to male rats (Tables 23.6 and 23.7) was
correlated with a dose-dependent massive increase in absolute liver weight
up to about 190 per cent of control at the highest dose level irrespective of
the treatment period and the test compound. This pronounced
hepatomegaly was paralleled by a comparably small two-fold elevation of
the microsomal cytochrome P450 contents and an about 50 per cent
decrease in total UDP- glucuronosyltransferase activity. Essentially no
changes were recorded for the cytochrome P450 dependent
ethoxycoumarin O-de-ethylase activity while microsomal epoxide
hydrolase activities appeared to vary, with slight increases in Compound C
and Compound D treated animals, no changes in Compound E treated
animals and even a dose-dependent reduction to 46 per cent of control in
rats treated with Compound F at 100 mg kg −1 (Table 23.6).
Strongly induced peroxisomal fatty acid β-oxidation activities for all
model compounds as well as lauric acid 12-hydroxylase activities tested for
Compounds E and F were accompanied by significant dose-dependent
decreases in glutathione S-transferase activities to 32, 51, 40 and 15 per
cent of control at the highest dose level tested for Compound C, D, E and