Toxicology of Industrial Compounds

318 ANTIOXIDANTS AND LIGHT STABILISERS: TOXIC EFFECT
contrast, although related to BHT, require higher molecular weights and
hydrophobicity in order to retain them in the polymer matrix. This can be
achieved, for example, by introducing alkyl chains or (esterified)
carboxyalkyl moieties in the para-position to the phenolic hydroxyl group
with variations in the aliphatic substitution pattern of the 2- and 6positions.
With these modifications the questions arose, whether or not the
toxicology of the chemically modified offspring would still be related to
that of the phenolic core of the BHT ancestor or completely different,
although a common metabolic degradation pathway to structural entities
resembling BHT could be anticipated. Clarification of this question was
expected to contribute to the understanding of the toxicology of an entire
class of phenolic antioxidants. A number of differentially esterified 4hydroxy-3,
5-dialkyl-phenylpropionic acid derivatives were subsequently
subjected to subchronic toxicity testing in rats with the result that the
effects encountered were largely dependent on the alcohol moiety used for
esterification and the size of the alkyl-substituent in the 3- and 5-positions:
most frequently, increased liver weights were encountered in compounds
with bulky 3,5-substituents such as tert-butyl. In some instances, however,
initial hepatomegaly was followed after several weeks or months of
treatment by increases in thyroid weights and a proliferation of the thyroid
follicular epithelium. The mechanism leading to the latter effect has been
investigated in detail using the di-ester of 3-tert-buty1–4-hydroxy-5-methylphenylpropionic
acid with ethylene glycol, Compound B, as a model
compound (Table 23.1).
Blood kinetics and blood metabolites
Compound B is a symmetrical di-ester compound (Table 23.1). When
administered at a single oral dose of about 10 mg kg −1 body weight to male
rats, 14 C-phenyl-labelled Compound B was readily adsorbed, and maximal
blood radioactivities were reached after 1 h. Thereafter, blood radioactivity
declined rapidly and only minute amounts were detected 48 h after
treatment. At any time point investigated Compound A, the free carboxylic
acid of Compound B, was the dominating blood metabolite, whereas the
parent compound constituted a minor component only (Table 23.2). These
findings are indicative of an efficient first pass hydrolysis and suggest that
the carboxylic acid metabolite, Compound A, might be responsible for the
toxicological profile of this antioxidant in the rat.
Liver enzyme induction
Compound B was administered in the feed to male rats at dose levels of 50,
150, 500 and 1000 ppm. After treatment for 14 days, absolute liver
weights were dose-dependently increased. Biochemically, this