Hazard assessment repeated 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). 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

Use of Information on Repeated Dose Toxicity in Hazard Assessment... 

In aU other situations, nonguideline studies cannot stand alone for a hazard assessment of a substance and thus cannot serve as the sole basis for an assessment of repeated dose toxicity, i.e., cannot be used to identify a substance as being of no concern in relation to repeated dose toxicity. 

The following general guidance is provided for the evaluation of repeated dose toxicity data in relation to hazard assessment (EC 2003) ... 

Use of Information from Repeated Dose Toxicity Studies in the Hazard Assessment of Immunotoxicity... 

The combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422, US-EPA OPPTS 870.3650) comprises a basic repeated dose toxicity study and a fertility/developmental toxicity screening test and, therefore, can be used to provide initial information on possible effects on a limited number of reproductive performance parameters. The test does not provide complete information on all aspects of reproduction, has a relatively short period of exposure, and does not provide evidence for dehnite claims of no reproductive effects, while positive results are useful for initial hazard assessment. Furthermore, results regarding repeated dose toxicity are influenced by the pregnant state of the female animals (see also Sections 4.7.3.1 and 4.7.5.2.2). 

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. 

The TDAR assay is believed to be one of the more predictive functional assays for assessing the immunotoxicity potential of drug candidates. This assay could be used to investigate the functional consequences of alterations seen in repeated-dose toxicity studies and/or clinical trials, and to provide an early read on the immunomodulatory potential of discovery candidates. The TDAR assay has been shown to predict immunotoxicity hazard. However, because of the inherent inter-animal variability seen in the TDAR particularly in outbred species, the assay should not be used as the definitive test but as an integral component of a weight-of-evidence approach for evaluating immunotoxicity risk. 

Intermediate-Duration Exposure. No reliable information is available on the effects of repeated-dose exposure in humans. Limited information is available on the effects of repeated inhalation and oral exposures to 1,1-dichloroethane in animals. The studies reviewed indicate that 1,1-dichloroethane is possibly nephrotoxic, but this effect has only been demonstrated at high doses in one of several species tested. No other toxic effects have been attributed to 1,1-dichloroethane following repeated-dose exposures in animals. An intermediate MRL could not be derived for any routes of exposure. More information on the systemic effects of repeated-dose exposures in animals, particularly by the inhalation route since this is the most likely route of human exposure, would be useful to determine whether nephrotoxic effects observed in one study are an actual result of exposure to 1,1-dichloroethane, to determine if 1,1-dichloroethane reacts like other chlorinated aliphatics (e.g., causes neuro-and liver toxicity), and to more fully assess potential human health hazards from repeated exposure to 1,1-dichloroethane. This latter justification is particularly important since repeated exposure to low levels of 1,1-dichloroethane may be of more concern than short-term exposure to very high levels based on the current use and/or disposal of this chemical. 

Bames JM. 1975. Assessing hazards from prolonged and repeated exposure to low doses of toxic substances. Brit Med Bull 31 196-200. 

Chemical speciation is especially critical when assessing mercury toxicity. Metallic mercury, because of its volatility, presents a hazard that seems to undergo repeated rediscovery. Its ability to seep into fissures in surfaces such as floors, from which it volatilizes, often leads to neglect of necessary precautions because it is not visible. Mercury vapor also reaches the brain far more readily than the ionic forms. Since the conversion of elemental mercury to mercuric ion by blood is a slow process compared to the time required for transport from lung to brain, and since elemental mercury seems to penetrate readily into brain,CNS tissue may contain ten times more mercury after vapor exposure than after a comparable intravenous dose of mercuric salt. The mercury is then retained in brain after oxidation because the... 

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