Repeat dose toxicity

GL31 Safety Repeat-dose toxicity test Studies to evaluate the safety of residues of veterinary drugs in human food Repeat-dose toxidly testing... 

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test OECD... 

The human and environmental protection goals in EUSES are human populations (workers, consumers, and man exposed via the environment) and ecological systems (micro-organisms in sewage treatment systems, aquatic ecosystems, terrestrial ecosystems, sediment ecosystems, and predators). Repeated dose toxicity, fertility toxicity, maternal toxicity, developmental toxicity, carcinogenic risk, and lifetime cancer risk can be calculated for the cases that literature data is available. 

Lazar (http //lazar.in silico.de/predict) is a k-nearest-neighbor approach to predict chemical endpoints from a training set based on structural fragments [43]. It derives predictions for query structures from a database with experimentally determined toxicity data [43]. Model provides prediction for four endpoints Acute toxicity to fish (lethality) Fathead Minnow Acute Toxicity (LC50), Carcinogenicity, Mutagenicity, and Repeated dose toxicity. 

Lazar [59] derives predictions for four endpoints Fathead Minnow Acute Toxicity (LC50), Carcinogenicity, Mutagenicity, and Repeated dose toxicity. 

Europe Note for Guidance on Repeated Dose Toxicity.8... 

Committee for Proprietary Medicinal Products (CPMP). Note for Guidance on Repeated Dose Toxicity (CPMP/SWP/1042/99). October 2000. 

Marrs TC, Colgrave HF, Edginton JA, et al. 1988. The repeated dose toxicity of a zinc oxide/hexachloroethane smoke. Arch Toxicol 62 123-132. 

Toxicity (e.g., acute, irritation, sensitisation and repeat-dose toxicity)... 

The dangerous properties of acute toxicity, irritation, corrosivity, sensitisation, repeated-dose toxicity and CMR are evaluated in terms of their potential toxic effects to workers, consumers and man exposed indirectly via the environment, based on the use for each stage in the lifecycle of the substance from which exposure can occur. Risk assessment is also required if there are reasonable grounds for concern for potential hazardous properties, e.g., from positive in vitro mutagenicity tests or structural alerts. The risk assessment involves comparing the estimated occupational or consumer exposure levels with the exposure levels at which no adverse effects are anticipated. This may be a quantitative risk assessment, based on the ratio between the two values, or a qualitative evaluation. The principles of human health risk assessment are covered in detail by Illing (a.30) and more briefly in Chapter 7 of (73). 

TABLE 2.7. Duration of Repeated Dose Toxicity Studies to Support Clinical Trials and Marketing3... 

Duration of clinical trials Minimum duration of repeated dose toxicity studies0 Duration of clinical trials Minimum duration of repeated dose toxicity studies1 0 ... 

Repeat-dose toxicity (subacute and chronic trials) ... 

Chronic and subchronic toxicity studies are conducted to define the dose level, when given repeatedly, that cause toxicity, and the dose level that does not lead to toxic findings. In Japan, such studies are referred to as repeated-dose toxicity studies. As with single-dose studies, at least two animal species should be used, one rodent and one nonrodent (rabbit not acceptable). In rodent studies, each group should consist of at least 10 males and 10 females in nonrodent species, 3 of each sex are deemed adequate. Where interim examinations are planned, however, the numbers of animals employed should be increased accordingly. The planned route of administration in human subjects is normally explored. The duration of the study will be dictated by the planned duration of clinical use (Table 2.14). 

TABLE 7.7. FDA Draft Recommendation for Type I Immunotoxicity Test That Can Be Included in Repeated Dose Toxicity Studies... 

Usually a functional observational battery (FOB) is integrated into a rodent (rat) repeat dose toxicity study to meet this requirement... 

Matsuzawa, T., Hashimoto, M, Nara, H., Yoshida, M., Tamura, S. and Igarashi, T. (1997). Current status of conducting function tests in repeated dose toxicity studies in Japan. J. Toxicol. Sci. 22 374—382. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

Duration of Repeated Dose Toxicity Studies to Support Phase 1 and Phase 2 Clinical Trials in the EU, and Phase 1, 2, and 3 Clinical Trials in the United... 

Minimum Duration of Repeated Dose Toxicity Studies... 

The commercial HBCD has shown low acute toxicity [6]. The minimum lethal dose is greater than 20 g/kg for dermal and oral administration [18]. Repeated dose toxicity was assessed by Van der Ven et al. [42] and revealed enhanced endocrine... 

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Original Guideline, adopted 22 March 1996)... 

Combined repeated dose toxicity smdy with the reproduction/developmental toxicity screening test (July 2000) 870.3700 Prenatal developmental toxicity smdy (August 1998)... 

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