Foetal toxicity

The water-soluble nickel salts are less teratogenic than the particulate nickel compounds, but also induce prenatal loss. No conclusion can be reached at the present time as to whether the embryonic and foetal toxicity of nickel is, in part, related to mutagenic properties [421],... 

Before administration of a NME to man, a mutagenicity test in bacterial cells (Ames test), with and without metabolic activation, and tests for chromosomal aberrations in mammalian cells should be negative. Any positive or equivocal results will require additional tests to be performed before proceeding to man. Studies of embryo-foetal toxicity should be performed before administration of a NME to women of reproductive potential. Studies of fertility, early embryonic development and pre- and post-natal development are not required at this stage of development neither are carcinogenicity studies. 

The term quality is defined by the following criteria purity, identity, content, galenic properties and temperature stability of a substance. The term safety is defined in relation to acute and chronic toxicity, foetal toxicity and fertility, mutagenic and carcinogenic potential. 

Toxicology Exposure is by inhalation. MMA is a strong irritant (eyes, mucous membrane and skin), and a toxicant affecting nerve cells and causing occupational asthma, foetal toxicities, and possibly cancer [59]. I ARC concluded that there is no adequate evidence proving the carcinogenicity of MMA [60]. 

One author proposed that the VAERS reports of foetal loss underestimated a synergistic foetal toxicity associated with the two-vaccine 2009/2010 influenza season [4P]. This issue of reporting bias through VAERS is an important one, and added to this is the inconsistency in quality and completeness of VAERS reports. With this in mind, and remembering that VAERS cannot determine whether a vaccine has caused an AE, the author s conclusions cannot be supported in the absence of any epidemiological studies investigating the hypothesis. 

Cardiomyopathy Embryo-foetal toxicity Hypersensitivity reactions/anaphylaxis... 

In doses of 1.2 mg Ni/kg and up to 20 mg Ni/kg, nickel chloride caused increased resorption rates and a number of malformations in murine foetuses, specific to the foetal skeletal system, as shown by atomic absorption [425]. It was believed that nickel chloride might influence embryos during the passage through the oviduct, with subsequent effect on the development after implantation [426]. Preimplantation mouse embryos have also been used to investigate toxic effects of nickel chloride on early embryo development in vitro, and a dose-dependent effect has been found [427]. 

The FDA allows women to enter carefully controlled and monitored trials in which adequate contraceptive measures and pregnancy testing are performed without requiring results from animal reproductive toxicity tests. In Japan and Europe, because of the high level of concern regarding imintentional exposure of the developing embryo or foetus, an assessment of fertility in a rodent, and embryo/foetal development in a rodent or non-rodent are required if women of childbearing potential are to be included in a Phase I trial. The FDA would expect such results to support Phase II and Phase III studies. 

Frieling WJAM, Heijink E, Tesh SA, et al. Embryo-foetal development toxicity of propylene glycol in NZW rabbits. Repro Tox 2000 14 562. 

Single and repeat dose toxicity studies (with later mainly in the rat and dog by oral or intravenous route and up to 1 year duration), reproduction toxicity (embryo-foetal studies in the rat and rabbit), battery of genotoxicity assays, carcinogenicity studies (by diet route in mouse and rat) plus ADME studies (single and multiple dosing)... 

Foetal nACh-R partial agonist (nACh-R potent antagonist) [toxic, skeletal muscle relaxant]... 

In some reproductive toxicity studies in experimental animals the only effects recorded may be considered of low or minimal toxicological significance and classification may not necessarily be the outcome. These include for example small changes in semen parameters or in the incidence of spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as are observed in skeletal examinations, or in foetal weights, or small differences in postnatal developmental assessments. 

Classification should not automatically be discounted for chemicals that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1. However, when a chemical is so toxic that maternal death or severe inanition results, or the dams are prostrate and incapable of nursing the pups, it may be reasonable to assume that developmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount the developmental effects. Classification may not necessarily be the outcome in the case of minor developmental changes e.g. small reduction in foetal/pup body weight, retardation of ossification when seen in association with maternal toxicity. 

Reproductive toxicity Fertility studies are not generally required during early clinical development unless there is good reason. Embryotoxicity/foetal development studies in two species are normally expected if women of childbearing potential are to be included in clinical trials interaction potential with oral contraceptives should be considered in this case. 

Parshad RK. 1999. Effects of selenium toxicity on oestrous cyclicity, ovarian follicles, ovulation and foetal survival in rats. Indian J Exp Biol 37 615-617. 

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