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Description of key information

Short description of key information on bioaccumulation potential result:

No single study on methyl salicylate (MeS) covers all the endpoints of basic toxicokinetics (absorption, distribution, metabolism and elimination). Several studies on MeS and related salicylates have been chosen to cover these endpoints between them. The key studies chosen are:

Absorption and Distribution: Yamagata (1976), Davison (1961) and Rainsford (1980).

Metabolism: Davison (1961), Emudianughe (1988) and McMahon (1989).

Excretion: Yamagata (1976), McMahon (1990)

Overall it can be concluded that all the salicylates share a common metabolic profile following initial ester hydrolysis to free salicylate.

Short description of key information on absorption rate:

The key studies chosen are a study in hairless mice, by Yamagata (1976) and in rats, by Megwa (1995)

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):
40

Additional information

Summary.

No single study on methyl salicylate (MeS) covers all the endpoints of basic toxicokinetics (absorption, distribution, metabolism and elimination). Several studies on MeS and related salicylates have been chosen to cover these endpoints between them. The key studies chosen are:

Absorption and Distribution: Yamagata (1976), Davison (1961) and Rainsford (1980).

Metabolism: Davison (1961), Emudianughe (1988) and McMahon (1989).

Excretion: Yamagata (1976), McMahon (1990)

Overall it can be concluded that all the salicylates share a common metabolic profile following initial ester hydrolysis to free salicylate, dependent on rate according to each sunbstance.

 

Dermal penetration:Yamagata (1976), Megwa (1995)

 

Basic toxicokinetics

The absorption, distribution and elimination of MeS by the oral and dermal routes was compared in hairless mice. Radiolabelled MeS was administered to femaleHRS/J (hr) hairless mice once by gavage or topically in a plaster for a period of from 30 minutes to 48 hours. Following gavage administration, blood level of radioactivity reached a peak at 30 minutes at which time blood concentration of salicylate was 106 μg/ml. Absorption following topical administration was slower, with peak blood level of radioactivity reached after 2 hours contact, and blood concentration of salicylate 8 μg/ml. Following gavage administration, blood concentration decreased rapidly from this peak, while the peak concentration for topical administration was followed by a gradual decrease due to ongoing absorption of radioactivity from the skin into the blood. Recovery of radioactivity over the 48 hour study period indicated that MeS was fully absorbed by this route, however by the dermal route only 35% MeS was absorbed at 24 hours and 40% at 48 hours.

Peak levels of radioactivity were reached in the tissues at the same time points as for absorption, indicating rapid distribution. Irrespective of route of administration, radioactivity levels were highest in the liver, kidneys and adrenals but low in the lungs, heart, spleen and pancreas, with the lowest level in the brain.

The majority of the absorbed dose was excreted in the urine within 48 hours regardless of route of administration, approximately 100% following oral administration and 97% following topical administration. Less than 3% was excreted in the faeces. This study did not attempt to identify metabolites (Yamagata, 1976).

The oral absorption, distribution and metabolism of MeS, NaS and ASA in rats, dogs and humans have been compared. In rats and dogs, MeS, NaS and ASA were all rapidly absorbed following oral administration even at high concentrations. NaS absorption was the most rapid, probably due to its higher water solubility. Absorption of MeS in humans was somewhat slower than for ASA, with total salicylate plasma concentration at 90 minutes approximately half that from ASA (Davison, 1961). Salicylic acid has also been shown to be rapidly absorbed after oral administration in rats (Rainsford at al., 1980).

Plasma analysis in rats showed rapid hydrolysis to free salicylate for MeS, NaS and ASA, resulting in comparable plasma concentrations of salicylate at 60 minutes post dosing, with no measurable parent compound. In humans, hydrolysis of MeS was slower and less complete, with 30% MeS remaining unhydrolysed at 15 minutes, and 21% at 90 minutes (Davison, 1961). These results indicate that following absorption, the initial metabolic step for all these salicylates (MeS, NaS and ASA) is hydrolysis to free salicylate. Since free salicylate is the principal species circulating in plasma following absorption of MeS, SA, NaS and ASA, it follows that data from these other salicylates are acceptable for read across to MeS for all systemic toxicological endpoints.

Rainsford et al (1980) compared the distribution of ASA, SA and the methyl ester of ASA () in rats. SA 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 SA versus ASA in mice after injection of these compounds. Davison (1961) detected salicylate in the brain of rats at 20 and 60 minutes after oral administration of MeS or ASA. Tjalve et al. (1973) showed that after intravenous administration in mice, SA was found in the placenta and readily passed into the fetuses. It can be concluded that salicylate is distributed widely in the body after administration of MeS and other salicylates.

A study in 4 human volunteers (Wolowich, 2003) gave a mean time to maximum serum concentration of salicylate of 2.4 hours, confirming the slower absorption in humans reported by Davison (1961).

A study on SA in rats (Emudianughe, 1988) revealed two major urinary metabolites, salicyluric acid and salicyl-glucuronic acid in addition to the free unchanged SA. Additionally, the results of this study showed no increase in the metabolism of SA over the course of the various stages of gestation in rats. In another study in rats, McMahon et al. (1989) showed that both SA and NaS are 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). Rainsford (1980) also confirmed the presence of small quantities of 2,5-dihydroxybenzoic acid as well as SA in the blood of rats dosed with SA.

McMahon et al. (1989) showed that SA 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. 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 able to pass through the placenta to reach the foetus (Levy, 1975).

Taken together these results show that MeS is well absorbed in several species of animal and distributed through several organ systems. It is metabolized initially to free salicylate then mainly to salicyluric acid and conjugated salicylic acid compounds, with a small proportion of oxidative metabolites . These metabolites and free salicylate are excreted almost entirely via the urine. The data from these studies are consistent with the metabolic pathways proposed for ASA (Graham, 2004), except that the first metabolic step for ASA is deacetylation, while that for MeS is hydrolysis.

The pathways of biotransformation of ASA, SA, MeS, NaS and other salicylate esters are considered to be the same following initial hydrolysis to free salicylate. In qualitative terms, types of adverse effects reported from all of these salicylates would be predicted to be similar, other than any related to non-acetylated ASA, supporting a read-across approach of toxicological data between these substances (see Rainsford,2004).

Dermal absorption

The absorption, distribution and elimination of MeS by the dermal route was compared with oral absorption in hairless mice (Yamagata, 1976). Radiolabelled MeS was administered once by gavage or applied topically for a period of 30 minutes to 48 hours to femaleHRS/J (hr) hairless mice. Approximately 35% of the dermal dose was systemically absorbed after 24 hours and 40% after 48 hours, compared with close to 100% absorption following oral administration.

The skin permeability of MeS was investigated in human volunteers (Yano, 1986). 0.5 mg MeS was applied topically to the intact skin of the forearm and occluded for 4 hours. Approximately 93% of the applied dose was absorbed mainly into the epidermis and less through the skin., for SA a maximum of 20% was determined when used in cosmetic ointments (SCCNFP, 2002)

A study on dermal absorption and metabolism of MeS in rats (Megwa 1995) demonstrated that MeS is readily absorbed and mainly hydrolysed to free salicylate during transit through the skin.

Systemic exposure to MeS following the 8 hour application of 2, 4 or 8 adhesive patches containing 75 mg MeS was measured in human volunteers (Martin, 2004). For the 8-patch group, the average maximum plasma concentration of MeS was approximately 30 ng/mL very low value in fact even if conversion to SA is not taken into consideration. The harmonic mean terminal half-life was 3.0 +/- 1.2 hours. Although it was not possible to determine the absolute dermal bioavailability, systemic exposure was considered to be low.

Overall, it can be concluded that close to 100% of a dermal dose of MeS is absorbed into the skin, with at maximum 40% being systemically distributed. A considerable degree of hydrolysis appears to take place during dermal absorption, so that the systemically distributed substance is primarily free salicylate.

Discussion on bioaccumulation potential result:

The absorption, distribution and elimination of MeS by the oral and dermal routes was compared in hairless mice. Radiolabelled MeS was administered to female HRS/J (hr) hairless mice once by gavage or topically in a plaster for a period of from 30 minutes to 48 hours. Following gavage administration, blood level of radioactivity reached a peak at 30 minutes at which time blood concentration of salicylate was 106 μg/ml. Absorption following topical administration was slower, with peak blood level of radioactivity reached after 2 hours contact, and blood concentration of salicylate 8 μg/ml. Following gavage administration, blood concentration decreased rapidly from this peak, while the peak concentration for topical administration was followed by a gradual decrease due to ongoing absorption of radioactivity from the skin into the blood. Recovery of radioactivity over the 48 hour study period indicated that MeS was fully absorbed by this route, however by the dermal route only 35% MeS was absorbed at 24 hours and 40% at 48 hours.

Peak levels of radioactivity were reached in the tissues at the same time points as for absorption, indicating rapid distribution. Irrespective of route of administration, radioactivity levels were highest in the liver, kidneys and adrenals but low in the lungs, heart, spleen and pancreas, with the lowest level in the brain.

The majority of the absorbed dose was excreted in the urine within 48 hours regardless of route of administration, approximately 100% following oral administration and 97% following topical administration. Less than 3% was excreted in the faeces. This study did not attempt to identify metabolites (Yamagata, 1976).

Discussion on absorption rate:

The absorption, distribution and elimination of MeS by the dermal route was compared with oral absorption in hairless mice (Yamagata, 1976). Radiolabelled MeS was administered once by gavage or applied topically for a period of 30 minutes to 48 hours to femaleHRS/J (hr) hairless mice. Approximately, a maximum of 35% of the dermal dose was systemically absorbed after 24 hours and 40% after 48 hours, compared with close to 100% absorption following oral administration.

The skin permeability of MeS was investigated in human volunteers (Yano, 1986). 0.5 mg MeS wasapplied topically to the intact skin of the forearm and occluded for 4 hours. Approximately 93% of the applied dose was absorbed into or through the skin.

A study on dermal absorption and metabolism of MeS in rats (Megwa 1995) demonstrated that MeS is readily absorbed and mainly hydrolysed to free salicylate during transit through the skin.

Systemic exposure to MeS following the 8 hour application of 2, 4 or 8 adhesive patches containing 75 mg MeS was measured in human volunteers (Martin, 2004). For the 8-patch group, the average maximum plasma concentration of MeS was approximately 30 ng/mL (based on 7 l blood this represents a total of 21 μg over 75 mg: 0.028%). The harmonic mean terminal half-life was 3.0 +/- 1.2 hours. Although it was not possible to determine the absolute dermal bioavailability, systemic exposure was considered to be low. This may be an underestimate, since the report appears to consider only MeS concentration, not total salicylate.

Overall, it can be concluded that close to 100% of a dermal dose of MeS is absorbed into the skin, with at maximum 40% being systemically distributed. A considerable degree of hydrolysis appears to take place during dermal absorption, so that the systemically distributed species is primarily free salicylate.