Salicylic acid

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
A publication by Rainsford et al (1980) has been chosen as key study for absorption, demonstrating that SA 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. Publications by Emudianughe (1988) and McMahon et al (1989) have been chosen as key studies for metabolism and elimination, demonstrating that SA is metabolized to two major urinary metabolites, salicyluric acid and salicyl-glucuronic acid and oxidative metabolites and other conjugated salicylic acid compounds.  All these metabolites as well as unchanged SA are eliminated almost entirely via the urine. A supporting study be Dalgaard-Mikkelsen (1951) demonstrated that elimination rate depends on urinary pH. Several publications also demonstrate that SA is the initial metabolite (hydrolysis product) for related salicylates (ASA, AME, NaS, MeS).  In addition to the key study by Rainsford et al (1980) a publication by Davison (1961) reporting hydrolysis of MeS to SA in humans, rats and dogs has been chosen as supporting study.
Short description of key information on absorption rate: 
An in vivo study by Bucks et al (1990) in rhesus monkey has been chosen as key study, with two in vitro percutaneous absorption studies (Bronaugh et al., 1989; Berner et al., 1990) with rat and human skin chosen as supporting studies.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

60

Additional information

The toxicokinetic profile of salicylic acid has been investigated in a range of studies, none of which completely fulfill all the criteria of current study protocols. Nevertheless, acceptable information from studies on SA itself and from related salicylates (methyl ester and sodium salt) as well as acetylsalicylic acid covers absorption, distribution, metabolism and elimination.

Salicylic acid is rapidly absorbed after oral administration (Rainsford at al., 1980).

Rainsford and his colleagues (1980) compared the distribution of acetylsalicylic acid (ASA), salicylic acid (SA) and the methyl ester of ASA in rats. Salicylic acid was found in the stomach, liver, kidney lungs, bone marrow, intestine, inflamed paws and spleen. The methyl ester of ASA was distributed in vivo very similarly to that observed with ASA and SA. Tjalve et al. (1973) confirmed that there was no difference between the distribution of salicylic acid versus acetylsalicylic acid in mice after injection of these compounds. Tjalve et al. (1973) also showed that after iv administration in mice, salicylic acid was found in the placenta and readily passed into the fetuses.

A study in rats (Emudianughe, 1988) revealed two major urinary metabolites, salicyluric acid and salicyl-glucuronic acid in addition to the free unchanged salicylic acid. Additionally, the results of this study showed also no increase in the metabolism of salicylic acid in the course of the various stages of gestation in rats. In another study in rats, McMahon et al. (1989) showed that salicylic acid or its sodium salt (NaS) is metabolized to oxidative metabolites (2,3- and 2,5 -dihydroxybenzoic acid), salicylicuric acid and other conjugated salicylic acid compounds (salicyl ester glucuronide or salicyl ether glucuronide). A study in rabbits (Dalgaard-Mikkelsen., 1951) demonstrated that the rate of excretion and proportion of urinary salicylate to conjugated salicylic acid metabolites depends on urinary pH.

Salicylate is the main metabolite produced from both MeS and ASA. Small quantities of 2,5-dihydroxybenzoic acid were also present in the blood of rats dosed with salicylic acid (Rainsford, 1980). The oral absorption and metabolism of Methyl Salicylate (MeS) and NaS in rats and humans have been compared with that of ASA (Davison, 1961). In rats, MeS, NaS and ASA are all rapidly absorbed on oral administration even at high concentrations. Plasma analysis in rats showed rapid hydrolysis to free salicylate for all three compounds, resulting in comparable plasma concentrations of salicylate at 60 minutes post dosing. On the other hand in humans, hydrolysis of MeS to SA was slower and less complete.

McMahon et al. (1989) showed that salicylic acid is excreted almost exclusively in the urine. Less than 1 % was found in bile (as unmetabolized SA), as exhaled carbon dioxide or in faeces. This study reported also a shift in urinary excretion at high concentrations, towards a higher proportion of oxidative metabolites in older rats.

Taken together these results show that salicylic acid is well absorbed in several species of animal and distributed through several organ systems. It is metabolized mainly to salicyluric acid and conjugated salicylic acid compounds, with a small proportion of oxidative metabolites . These metabolites and free unchanged salicylic acid are excreted almost entirely via the urine. Salicylic acid is able to pass through the placenta to reach the foetus.

In the Rainsford book on aspirin and salicylates (2004) and reported in the ASA dossier:

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 developmental effects evaluation of human health protection. (see exposure related observations)

When comparing human and rat blood levels (see 2d joint document before), 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.

Discussion on absorption rate:

An in vivo study by Bucks et al (1990) in rhesus monkey has been chosen as key study. This demonstrated that dermal application of salicylic acid is followed by significant absorption of salicylic acid (approximately 60% of a single dose and approximately 80% for 14 days of repeated doses). Two supporting in vitro percutaneous absorption studies (Bronaugh et al., 1989; Berner et al., 1990) with rat and human skin showed that salicylic acid is absorbed through skin without dermal metabolism.