Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

In a study on rats, a big proportion of a single oral dose of 14C test substance to rats is eliminated in 24 days: 89.4-97.5% of the label is excreted in the faeces (much of this is eliminated in the first 4 days after dosage), 1% in the urine and < 0.1% in the expired gases. 3.46 and 3.42% of 14C respectively are present in the carcass and viscera of male and female rats after removal of the gut. Rats do not show a sex difference in the pattern of elimination of the test substance and its metabolites.
After ingestion of [14C] test substance the fatty tissues account for the retention of 14C.
Measurement of 14C in the bile of animals with biliary fistulae in conjunction with other data implies that one-fifth of a single dose of [14C] test substance is absorbed. 87% of 14C in the faeces is due to unchanged test substance, 5% to the quinone methide, 5% to the free acid and 3% to an unidentified polar constituent. Three-fifths of 14C in the urine is due to 3,5-di-tert.-butyl-4-hydroxybenzoid acid and the remainder to the ester glucuronide. In several animals, one-half of 14C in the bile is due to the free acid, one quarter to the ester glucuronide and the remainder to unchanged antioxidant, whereas, in others, all of 14C in the bile is due to test substance. 97% of 14C in the body fat is due to unchanged antioxidant and the remainder to the free acid.
Up to 20% of a single oral dose of the test substance is absorbed in rats: 13-14% is metabolized. 3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for > 5% of a dose of the test substance, 3,5-di-tert.-butyl-4-hydroxybenzoyl-β-Dglucopyranosiduronic acid for < 0.4%, the quinone methide for > 5% and an unidentified compound for < 3%.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

A reliable study in rats (Hathaway and Wright, 1965), a big proportion of a single oral dose of 14C test substance to rats is eliminated in 24 days: 89.4-97.5% of the label is excreted in the faeces (much of this is eliminated in the first 4 days after dosage), 1% in the urine and < 0.1% in the expired gases. 3.46 and 3.42% of 14C respectively are present in the carcass and viscera of male and female rats after removal of the gut. Rats do not show a sex difference in the pattern of elimination of the test substance and its metabolites.

After ingestion of [14C] test substance the fatty tissues account for the retention of 14C.

Measurement of 14C in the bile of animals with biliary fistulae in conjunction with other data implies that one-fifth of a single dose of [14C] test substance is absorbed. 87% of 14C in the faeces is due to unchanged test substance, 5% to the quinone methide, 5% to the free acid and 3% to an unidentified polar constituent. Three-fifths of 14C in the urine is due to 3,5-di-tert.-butyl-4 -hydroxybenzoid acid and the remainder to the ester glucuronide. In several animals, one-half of 14C in the bile is due to the free acid, one-quarter to the ester glucuronide and the remainder to unchanged antioxidant, whereas, in others, all of 14C in the bile is due to test substance. Only a low percentage of the test substance was retained in body fat. 97% of 14C in the body fat is due to unchanged antioxidant and the remainder to the free acid.

Up to 20% of a single oral dose of the test substance is absorbed in rats: 13-14% is metabolized. 3,5-di-tert.-butyl-4 -hydroxybenzoic acid accounts for > 5% of a dose of the test substance, 3,5-di-tert.-butyl-4-hydroxybenzoyl-βDglucopyranosiduronic

acid for < 0.4%, the quinone methide for > 5% and an unidentified compound for < 3%.

In an additional unreliable study on monkeys (Smith, 1970) the levels of14C activity in blood, plasma, urine, faeces and tissues have been determined in two monkeys which were dosed daily in the diet for 31 days with unlabelled substance then on day 32 intubated with approximately 130 mg/kg of a mixture of unlabelled & radiolabelled test material in corn oil. One animal was sacrificed at 24 hours, and the other at 66.5 hours, after treatment.The blood and plasma levels reached a maximum at 8 hours and showed little decline in the next 16 hours. The blood level dropped rapidly in the 24 to 48 hours interval and then fell more slowly towards 66.5 hours.The test material exhibits a low bioaccumulation potential, with the total distribution of 14C material in tissues being 1.56% after 66.5 hours.

Results from old unreliable in vivo pharmacology studies indicate that the substance undergoes much better absorption from non-aqueous media.

It is anticipated that absorption via the oral route is higher than absorption after dermal or inhalation exposure due to the emulsifying function of bile acids and longer contact time and surface area in the GI tract.