O-acetylsalicylic acid

Endpoint summary

Description of key information

A publication by Rainsford et al (1980) has been chosen as key study for absorption, demonstrating that ASA is readily absorbed. This publication and another by Tjalve et al (1973) have been chosen as key studies for distribution, demonstrating that SA is distributed in several organ systems, including via the placenta to the foetus.  Finally a book was published in 2004 by Rainsford; containing too mainy papers to be carefully analysed, but we have summarised chapter 4 related to this issue. Chap 4 pp121 Pharmacokinetics and Metabolism of the Salicylates
G.G. Graham, M.S. Roberts, R.O. Day and K.D. Rainsford,2004 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

80

Absorption rate - dermal (%):

1

Additional information

Acetyl-salicylic acid, as Salicylic acid, is rapidly absorbed after oral administration (Rainsford at al., 1980), they compared the distribution of acetylsalicylic acid (ASA), salicylic acid (SA) and the methyl ester of ASA in rats.See for further details the joint summary.

In vivo in the rat there is uptake of aspirin and salicylate into the stomach mucosa, with the acetyl moiety of aspirin binding covalently to proteins and other molecules in the stomach wall, indicating some presystemic metabolism in the stomach in this species (Morris et al., 1973; Rainsford et al., 1983). This gastric metabolism of aspirin is consistent with its gastric toxicity (Rainsford-1980: at least at 100 mg/kg while Thromboxane inhibition is present at 10mg /kg (Hung, 1998). The major site of presystemic metabolism of aspirin in man is in the liver (Rowland et al., 1972). There is a marked species-dependence in the binding of salicylate to serum proteins, with high binding in man, rhesus monkey, rabbit and guinea pig, while several other species, including the rat, mouse and dog, have much lower binding (Sturman and Smith, 1967). There are considerable interspecies differences in the activity of plasma aspirin esterase, with cats and rabbits showing approximately the same esteratic activity as humans while rats have a higher and dogs a lower activity than man (Morgan and Truitt, 1965). Pharmacokinetics of aspirin Unchanged aspirin can be detected in plasma for about 1 hour after its intravenous or oral administration. Following its intravenous administration in man, it has a distribution half-life of about 3 minutes, an elimination half-life of 10 minutes and a clearance of about 800 ml blood/min (Rowland and Riegelman,1968). Aspirin is hydrolysed enzymatically in blood, but its clearance in blood accounts for only about 15 per cent of the total body clearance of the drug and the bulk of the clearance is considered to occur in the liver (Rowland et al., 1972). By contrast, the clearance of aspirin in the rat is dose-dependent and at a low dose (40 mg/kg) is slightly greater than hepatic blood flow, indicating significant extra hepatic hydrolysis (Wientjes and Levy, 1988). Although these differences, rat and rabbit have some common pathways. All theses effects indicated that it is difficult to extrapolate from animals to human, nevertheless the rabbit is more in line with Epidemiology, with 2 major points:

- Binding to proteins.

- Non-ion trapping and no accumulation of SA in embryos at morphogenesis time.

This makes the rat a non-relevant species for reprotoxicity evaluation of human health protection.(see exposure realated observations)

When comparing human and rat blood levels (see 2d joint document), there are comparable at equivalent doses (allometric scaling factor), while they are higher in human at the same dose and even higher when comparing fetal blood levels. This further indicate that abnormalities seen in rat are not seen in humans, certainly due to different factors developed in toxicokinetics and reprotoxicity sections.