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1. Introduction
Reproductive health is influenced by environmental toxicants, including pesticides [1,2,3]. The declared active ingredients (dAI) of pesticide formulations are not applied in their isolated form in agricultural use. Other substances (co-formulants) are also added, in order to modify the physico-chemical properties or to improve penetration [4] or stability [5,6] of the dAIs. The identity of the co-formulants (declared as inert) is generally kept confidential. Moreover, they are not used in medium or long term in vivo toxicity tests of pesticides on mammals for the establishment of their acceptable daily intake (ADI). However, pesticide formulations and co-formulants alone have been demonstrated to be up to 1000 times more toxic to human cells than their dAI at 24 h exposure [7,8].
Among pesticides, glyphosate-based herbicides (GBHs), such as Roundup (R), are the most frequently used worldwide, and their residues are common contaminants of ground and surface water [9] and in food and feed [10]. This is partly due to pre-harvest desiccation treatment of non-transgenic cereals with GBHs [10], but mostly because they are sprayed on the 80% of genetically modified edible plants purposely designed to tolerate R [11] and, thus, contain its residues [12]. When other pesticides are generally allowed in edible plants at levels around 0.01-0.1 ppb [13], glyphosate and its metabolite AMPA have among the highest maximum residue limits (MRL), with up to 500 ppm authorized in some genetically modified feed [14]. It is well known that GBHs and their co-formulants, such as polyethoxylated tallow amine (POEA), are more toxic than glyphosate (G) alone, both in in vitro [15,16,17,18,19] and in vivo studies [20,21,22,23]. Thus, co-formulants may contribute to reproductive side-effects [24,25,26,27,28,29]. Co-formulants added to GBHs in formulation differ between countries and manufacturers. As a result of this variability in co-formulants, and since most of them are not compulsorily declared, the formulation and the dAI are often treated as the same substance, and co-formulants are not target ingredients in (eco)toxicological studies [30,31,32,33,34]. This results in a misconsideration of GBH toxicities in the literature, where different biological effects of formulations due to different co-formulants are possible.
The objective of this work is to test the cellular endocrine disrupting effects of co-formulants in GBHs below toxic levels, both alone and in formulations (mixtures of co-formulants...