Repeated dose toxicity

1 Oral. Sasser et aZ. dosed male and female Sprague-Dawley rats (12 of each gender per dose group) with SM dissolved in sesame oil for 5 days per week for 13 weeks. The doses used were 0 (control), 0.003, 0.01, 

2 Inhalation. McNamara et al studied 6 dogs, 12 rabbits, 30 guinea pigs, 140 rats and 140 A/J mice, housed in a chamber and continuously exposed to 0.001 mg m of SM vapour for between 1 and 52 weeks. Temperature fluctuated with adjacent room temperature but the chamber was heated during cold weather. The same species and numbers of animals were housed in another chamber and exposed to 0.1 mg m of SM vapour 5 days per week, 6.5 hours per day plus 0.0025 mg m for the remaining 17.5 hours per day. 

Blood analysis was only carried out in dogs and rabbits, exposed to either dose of SM. There were no effects on RBC count, total and differential WBC counts, haematocrit or haemoglobin. There were also no changes in blood clinical chemistry markers including total protein, urea, serum glutamic pyruvic transaminase, lactic dehydrogenase, alkaline phosphatase, creatinine, bilirubin, sodium chloride, potassium and carbon dioxide. 

Guinea pigs exposed to air, 0.001 or 0.1 mg m SM for between 1 and 52 weeks were used in sensitisation studies. At 1, 2, 4, 8, 16, 32 and 52 weeks post challenge six animals per chamber were removed and challenged again with 7.9 pg of SM in castor oil onto the skin. At this dose, sensitised animals should show signs of erythema, oedema and necrosis. There was no evidence of sensitisation. 

There are no controlled, repeat dose studies in humans, but the exposure of workers to low doses of SM during its manufacture demonstrates that repeated exposures can produce serious long term toxic effects. 

Repeated dose toxicity studies differ with respect to duration. In principle, any duration is possible, but for the sake of harmonization it has become necessary to limit the study durations to a number of standard durations in the test guideline studies. 

The term repeated dose toxicity comprises the adverse general (i.e., excluding reproductive, genotoxic, or carcinogenic effects) toxicological effects occurring as a result of repeated daily dosing with, or exposure to, a substance for a part of the expected life span (subacute or subchronic exposure) or for the major part of the fife span, in case of chronic exposure (EC 2003). 

The terms subacute, subchronic, and chronic are often used in the context of repeated dose toxicity. These terms are not used consistently however, there is consistency in the use of the terms subchronic and chronic by OECD, US-EPA, and EU, see below. 

The term subacute is not an OECD term. Presumably it relates to a study, which is shorter than a subchronic study, i.e., in OECD terms, it would be a study shorter than 90 days. 

In the test guidelines for 90-day dermal (OECD TG 411) and inhalation (OECD TG 413) toxicity studies, the following definition in relation to the term subchronic is provided Subchronic dermal/inhalation toxicity is the adverse effects, which follow repeated daily dermal application/ inhalation of a chemical for part (not exceeding 10%) of a life span.  

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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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