Reproduction, toxic/adverse effects testing

Toxaphene is extremely toxic to freshwater and marine biota. In laboratory tests of 96-h duration, 50% mortality was recorded for the most sensitive species of freshwater and marine teleosts, marine crustaceans, and freshwater insects at nominal water concentrations of less than 10 pg/L of toxaphene, and, in several cases, less than 1 pg/L (Table 27.2). Bioassays of longer duration, based on exposure of aquatic organisms for the entire or most of the life cycle, produced significant adverse effects on growth, survival, and reproduction at toxaphene concentrations between 0.025 and 1.0 pg/L (Table 27.3). Toxaphene was most toxic to freshwater fishes in soft water at elevated temperatures (Saleh 1991). Based on its high toxicity and extensive use, it is not surprising that toxaphene was considered a major cause of nationwide fish kills in 1977 (USEPA 1980b). 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

The acute toxicity of emorfazone was found to be equal to or less than that of aminopyrine depending on animal models used [45]. From chronic toxicity tests [46,47], safe doses of 30 mg/kg per day (rats) or 120 mg/kg per day (dogs) were deduced. In rats, no significant effects of (3) on the reproductive activity or newborn development were observed [48-50], nor were adverse effects on the embryos found when (3) was given to rabbits, rats or mice during the period... 

Data from repeated dose toxicity studies in which there are marked adverse effects on the reproductive organs (usually the testes) can also be used to identify a substance as being toxic to reproduction. Data from such studies cannot be used to identify a substance as being of no concern in relation to reproduction. 

It is important to consider both in vitro and in vivo studies for evaluation of altered sexual function and fertility. In vivo studies are the primary basis for such reproductive toxicity testing, but in vitro studies (e.g., detailed studies on receptor interactions) that can provide a mechanistic explanation for the adverse effects observed in vivo are also useful. 

The corpus luteum arises from the ruptured follicle and secretes progesterone, which has an important role in the estrous or menstrual cycle. Luteal progesterone is also required to maintain early pregnancy in most mammalian species, including humans (Csapo Pulkkinen, 1978). Therefore, establishment and maintenance of normal corpora luteaare essential for normal reproductive function. However, with the exception of evaluations to establish their presence or absence, these structures are not evaluated in routine testing. Increased rates of follicular atresia and oocyte toxicity may lead to premature menopause in humans. Altered follicular development, failure to ovulate or altered corpus luteum formation and function can disrupt cyclicity, reduce fertility and interfere with normal sexual behaviour. Therefore, significant increases in the rate of follicular atresia, evidence of oocyte toxicity, interference with ovulation or altered corpus luteum formation or function should be considered adverse effects. 

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