Toxic to reproduction

BASE SET Mutagenicity Toxicity to reproduction Toxicity to algae Acute daphnia and fish toxicity Abiotic and readily biotic degradability Additional physico-chemical properties 1 t/annum or 5 t cumulative... 

S5(R2) Detection of Toxicity to Reproduction for Medicinal Products Toxicity to Male Fertility Biotechnological Products... 

Meanwhile the first tranche of the registration is done for all chemicals with a market volume of more than 1,000 Mg/a and for chemicals which have a high concern out of hazardous reasons (e.g., carcinogenic, mutagenic, or toxic to reproduction (CMR)). By the REACH deadline of 30 November 2010 for the first tranche, 24,675 registration dossiers were submitted for 4,300 substances including nearly... 

European Commission - Enterprise and Industry DG - Pharmaceutical Unit Detection of Toxicity to Reproduction for Medicinal Products Including Toxicity to Male Fertility (Directive 75/318/EEG - June 1996). Available at http //pharmacos.eudra.org/F2/eu-dralex/vol-3/pdfs-en/3bs4aen.pdf. 

S5A S5B Detection of toxicity to reproduction for medicinal products Reproductive toxicity to male fertility Jun 93... 

FDA International Conference on Harmonization Guideline on detection of toxicity to reproduction for medicinal products Addendum on toxicity to male fertility. Federal Register, April 5, 1996, Vol. 61, No. 67. 

The reproductive/developmental toxicity screening test can provide initial information on possible effects on reproduction and/or development and may make it possible to identify a substance as being toxic to reproduction, i.e., the test gives a clear positive result. However, this test offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. In addition, because of the study design (e.g., relatively small numbers of animals per dose level, relatively short smdy duration), the test will not provide evidence for definite claims of no effects. 

If peri-postnatal tests, developmental neurotoxicity smdies, or specific male or female fertility studies are available they can be used to identify a substance as being toxic to reproduction. Data from such studies alone cannot be used to identify a substance as being of no concern in relation to reproduction. 

UFm accounts for the quality and relevance of the database, i.e., accounts for the uncertainties in the establishment of a NOAEL for the critical effect. The UFm includes elements such as (1) the quality of the database, e.g., data on specific toxic endpoints are lacking or inadequate, default value of 1-10 (2) route-to-route extrapolation, e.g., no studies using the appropriate exposure route are available, no default value (3) LOAEL-to-NOAEL extrapolation, e.g., a NOAEL cannot be established for the critical effect, default value of 10 (4) subchronic-to-chronic extrapolation, e.g., no chronic studies on which to establish the NOAEL are available, default value of 10 and (5) nature and severity of toxicity, e.g., the critical effect is toxicity to reproduction, carcinogenicity or sensitization, default value of up to 10. A default value for UFm has not been recommended however, a value from 1 to 100 is generally used. The value is evaluated case-by-case based on expert judgment. 

The risk characterization is carried out by quantitatively comparing the outcome of the hazard (effects assessment) to the outcome of the exposure assessment, i.e., a comparison of the NOAEL, or LOAEL, and the exposure estimate. The ratio resulting from this comparison is called the Margin of Safety (MOS) (MOS = N(L)OAEL/Exposure). This is done separately for each potentially exposed population, i.e., workers, consumers, and man exposed via the environment, and for each toxicological endpoint, i.e., acute toxicity, irritation and corrosion, sensitization, repeated dose toxicity, mutagenicity, carcinogenicity, and toxicity to reproduction. 

There were major differences in the protocol designs for rodent studies between Japanese and European studies. These were resolved by the ICH, which in 1993 published a guideline entitled Detection of Toxicity to Reproduction for Medicinal Products. ... 

Toxicity to Male Fertility An Addendum to the ICFl Tripartite Guideline on Detection of Toxicity to Reproduction for Medicinal Products, as amended in November 2001) in a one-month repeat-dose study, a premating treatment interval of 2 weeks for both sexes can be used. The treatment period requires justification. Dosing should continue through mating and at least through implantation in the females. 

ICH (2005) ICH harmonised tripartite guideline detection of toxicity to reproduction for medicinal products toxicity to male fertility S5(R2). http //www.ich.org/fileadmin/ Public Web Site/ICH Products /... 

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). 

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