Registration Dossier

Administrative data

Description of key information

Human experience with SA is limited to industrial exposure and its use in cosmetology, but as a major metabolite of ASA, this molecule has a long experience in human and can be used in read across although SA do not bear the anti-thrombotic property of ASA.

Additional information

Apart from its acute oral toxicity, ASA (o-acetylsalicylic acid) is not classified and the major part is sold as an over the counter (OTC) drug. There are some differences between species among developmental effects, the rat being very sensitive or not relevant for human, according to several species differences and limited information on true maternal toxicity. As such the NOAEL found in reports are not in line with the general repeated toxicity NOAEL, nor the known ulcerogenic activity of ASA in rat and human.

In order to have a correct view on epidemiological data, reported or not in previous reviews, we have requested the support of an expert epidemiologist, who made a critical analysis of the data (see 1st document attached). His report indicates no link between ASA use and deleterious effects at low and high human doses. "Low dose" relates to antithrombotic regular use, while "high dose" refers to antalgic more sporadic use. Note the natural exposure trough Food to salicylates: The values for salicylate in foods that we have obtained work out to a range from about 10 mg to 200 mg/day salicylate in Western diets. This is of the same order of magnitude as the challenge dose of salicylate used in clinical testing (60), usually a 300-500 mg aspirin tablet. The usual adult pharmacological dose of aspirin is 600 -1000 mg two tablets) at a time, often several times a day. Previous figures for salicylates in most foods are so much smaller than this (20-300 mg) that it is difficult to see how the food could have similar effects to salicylate medication in sensitive individuals. (Swain, 1985, Research). There are a large set of publications indicating the benefit of daily ASA low doses to improve cardiovascular diseases and cancers. As such, with more than one-century use, ASA human experience, with known upper limits, had proven its safety for Human health. This is certainly why SA (salicylic acid), together with other salicylates, is now agreed as flavouring ingredients quantum satis (Regulation EU No 872/2012 of 01/10/2012). Discussion: As a final conclusion on reprotoxicity data evaluation, no adverse effect of aspirin treatment can be considered as established during pregnancy, either at low (150 mg daily) or higher usual dose. Low-dose aspirin prevention of pre-eclampsia and associated adverse outcome may be modestly effective, although some uncertainties remain on the time window bringing such benefit with respect to possible adverse effects, e. g., mother or infant bleeding. (Benefit in case of thrombosis) Humans are exposed to therapeutic doses (up to 5g /day for 5 days as analgesic or anti-pyretic and up to 360 mg /d as or long term use for anti-thrombotic effects), far over potential occupational or use exposures. ASA is not restricted during the 1st trimester of pregnancy when morphogenesis is occurring. The recommendation for non-use in pregnancy relates to the 3d trimester due to a possible risk of bleeding in general population, although low-dose aspirin has been shown to have beneficial effects on women who are at risk for pregnancy-induced hypertension and preeclampsia (hypertension plus proteinuria or edema) and on their offspring (Helms, 2009).

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, as in the case of ASA, certainly due to different factors developed in toxicokinetics and reprotoxicity sections.