OECD and ICH

ICH Stage FDA Guidelines Great Britain and EEC Guidelines Japanese Guidelines EPA OPPTS, OECD and FDA Redbook Guidelines... 

In 1985 it was published [1] that stevioside was completely safe but that metabolically activated steviol was mutagenic in a "Forward Mutation Test". Steviol had to be applied together with the microsomal fraction of liver of animals treated with carcinogenic compounds (polychlorinated biphenyl or phenobarbital plus 5,6-benzoflavone). This publication has led to a confusing discussion between advocates and opponents of the use of Stevia or stevioside. To unravel the problem we must consider the opinion of authoritative international organisations such as OECD (Organisation for Economic Co-Operation and Development) and ICH (International Council of Harmonisation). To accept new substances as food three different mutagenesis tests are accepted and required by the OECD as well as by the ICH. These can be seen in Table 1. 

ICH guidelines specifically require three genotoxicity assays for all devices (see Table 6.2). The assays should preferably evaluate DNA effects, gene mutations and chromosomal aberrations, and two of the assays should preferably use mammalian cells. Guidance for providing tests for selection to meet these needs are the OECD guidelines, which include 8 in vitro and 7 in vivo assays. 

The ICH, OECD, FDA, and EPAhave issued guidance documents (1-4) for the conduct of embryotoxicity or prenatal toxicity studies. 

With respect to pharmaceuticals, the mouse is cited as an alternative species in the ICH S5(R2) guideline for the detection of toxicity to reproduction for medicinal products and toxicity to male fertility (2). Since the ICH guideline is also cited in other guidance documents (3, 4), it is clear that the mouse should be considered for teratology type (see Note 1) studies. In addition, although not specifically mentioned in other guidelines (OECD, FDA, EPA, etc.), the mouse may be an appropriate rodent model for products from the food and chemical industries if the choice is justified based on the available pharmacokinetic or metabolic information etc. (5-8). 

The ICH guidances complement the details of study designs outlined in the OECD guidelines. Additionally, they inform about the top concentrations for in vitro tests and the expected levels of cytotoxicity, and about repeat or confirmatory testing and the proof of target tissue exposure to the test article in the in vivo studies. 

Apart from various deviations in the study conduct of the following OECD test guidelines from the ICH principles of drug testing, the predominating difference is the much more extended duration of exposure to the test compound in the OECD test procedures, taking into consideration the uncontrolled and longer... 

This was adopted in 1995 (OECD 1995c). In principle this test is a combination of the study for effects on fertility and early embryonic development (also called fertility study) and the study for effects on embryo-fetal development for drugs (also called teratogenicity study ), of the ICH test guideline for drags. The study procedure is extended up to four days after parturition. The experimental male animals are continuously exposed to the chemical up to the end of the mating attempts and the females are continuously exposed throughout the study up to day four after parturition. 

International Organization for Standardization (ISO) www.iso.ch International Conference on Harmonization (ICH) www.ich.com Organization for Economic Cooperation and Development (OECD) www.oecd.org... 

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