Subacute/subchronic/chronic

Toxicological report (acute, subacute, subchronic, chronic toxicity, accumulation). 

The Federal Office of Public Health (FOPH) classifies chemical substances in terms of acute oral toxicity in the rat, and other available data such as skin and/or inhalation toxicity, skin and eye irritation/corrosive effects, subacute/subchronic/chronic toxicity, carcinogenicity/mutagenicity/teratogenicity and human exposure. Substances are placed in one of 5 classes ranging from Category 1 (most hazardous) to Category 5 (least hazardous). 

Subacute/Subchronic/Chronic studies 8e Checklist Subacute o Checklist to Determine Whether a Subacute/Subchronic/Chronic Study is 8(e) Reportable... 

Study is reportable based on criteria on Subacute/Subchronic/Chronic Study checklist. ... 

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. 

Duration extrapolation subacute to chronic, a default value of 6 subchronic to chronic, a default value of 2 local effects by inhalation, a default value of 1... 

Subacute-to-subchronic Subacute-to-chronic Subchronic-to-cbronic... 

Vermeire et al. (1999) reviewed several studies comparing NOAELs from chronic and subacute/subchronic studies in order to evaluate the distribution of the extrapolation factor for duration of exposure. The ratios of observed NOAELs from oral studies using historical data for various compounds were calculated. The most likely distribution of the ratios was considered to be lognormal and the parameters of the distributions of the ratios were estimated, see Table 5.8. 

Subacute/Subchronic-to-Chronic Oral NOAEL Ratios... 

The authors noted that it may be expected that the NOAELs from subacute/subchronic smdies tend to be larger than NOAELs from chronic studies and it was considered that the GM ratios for the NOAELs assessed in the studies most likely overestimated the median of the distribution of the extrapolation factor for duration of exposure. The authors also noted that it is very likely that the databases used in these studies overlap each other significantly. It was also pointed out that the distributions presented in Table 5.8 were based on rather variable exposure periods for the subchronic NOAELs, included interspecies variation (no matching for species) for... 

KEMl (2003) suggested that, if necessary, extrapolation can be performed from subchronic to chronic exposure and that such an extrapolation should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001). If the 95th percentile is chosen, i.e., covering 95% of the substances compared, the corresponding assessment factor is 16. Extrapolation from subacute to chronic exposure should preferably not be performed, but if it is necessary a similar approach is suggested for this extrapolation, an assessment factor of 39 corresponds to the 95th percentile based on the lognormal distribution of NOAEL ratios from subacute and chronic exposure studies in Vermeire et al. (2001). 

WHO/IPCS (1994, 1996, 1999) did not consider an extrapolation factor for duration of exposure specifically, but the uncertainty related to this element is included in a broader defined additional factor addressing the adequacy of the overall database (Section 5.9). The US-EPA (1993) has adopted the 10-fold factor to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs. This default value has later on been reconfirmed (US-EPA 2002) when only a subchronic duration smdy is available to develop a chronic reference value no chronic reference value is derived if neither a subchronic nor a chronic smdy is available. For systemic effects, ECETOC (2001) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. KEMl (2003) suggested that extrapolation from subchronic to chronic exposure should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001) with an assessment factor of 16 covering 95% of the substances compared and for extrapolation from subacute to chronic exposure, with an assessment factor of 39 covering 95% of the substances. 

A default assessment factor of 10 has been used traditionally for the extrapolation from a LOAEL to a NOAEL. Some analyses have been performed in order to evaluate the size of an appropriate assessment factor for the LOAEL-to-NOAEL extrapolation, based on evaluations of LOAEL/NOAEL ratios. A number of evaluations have been based on data from Weil and McCollister (1963) and adapted by Dourson and Stara (1983). Some evaluations found that this analysis supports that a factor of 10 or lower is adequate while others found the factor of 10 to be overly conservative as the LOAEL rarely exceeded the NOAEL by more than about 5-6 fold and was typically closer to a value of 3. The analysis on LOAEL/NOAEL ratios performed on LOAEL/NOAEL ratios showed 95th percentiles of 9, 16, and 11 for subacute, subchronic, and chronic exposure durations, respectively, supporting the 10-fold factor to account for about 95% of the chemicals evaluated. 

Subacute, subchronic, and chronic studies have been conducted in experimental animals to test the toxicity of HFC-134a (Kennedy 1979 Riley et al. 1979 Silber and Kennedy 1979b Hext and Parr-Dobrzanski 1993 Hext 1989 Alexander and Libretto 1995 Collins et al. 1995). Those studies are summarized in Table A-4. 

Ames Test - Negative, with and without metabolic activation No subacute/subchronic or chronic toxicological data are available for BTF. PCBTF (CAS 98-56-6)... 

It is common practice for toxicologists to differentiate exposure to chemicals based on the dose and the duration of exposure. Lour timeframes have been used to define duration of exposures acute, subacute, subchronic, and chronic. It is useful in light of today s interest in long-term, low-levef exposures to clarify these terms. Acute exposure is defined as exposure to a chemical for less than 24 h. Subacute exposure refers to an exposure of 1 month or less, subchronic for 1 to 3 months, and chronic for more than 3 months. These exposures can be by any route for most chemicals it is the oral route with the chemical given in the diet. However, the limited animal studies using nerve agents have usually employed parenteral administration... 

No review of subacute, subchronic, or chronic toxicity of chemical warfare nerve agents would be complete without discussion of the significant paper by Munro et al. that reviewed both animal and human studies of the nerve agents tabun (GA), sarin (GB), and VX. These studies included subacute, subchronic, and chronic toxicity studies in animals. Special attention was paid to the phenomenon of Organophosphorus-Induced Delayed Neuropathy (OPIDN). Reproductive toxicity and carcinogenicity tests were reviewed as well as in vitro studies of mutagenicity. Munro et al. s findings can be summarized as follows ... 

Intracutaneous reactivity Systemic toxicity (acute) Subacute/subchronic toxicity Genotoxicity Implantation Hemocompatibility Chronic toxicity Carcinogenicity Reproductive toxicity Biodegradation Toxicokinetics Immunotoxicity... 

These so-called subacute or subchronic toxicity studies involve the repeated application of a test substance to animals, typically for a period of 30 or 90 days. The time pattern is thus an intermediate one between acute and chronic toxicity. To test a substance for subacute or subchronic toxicity, it is mainly applied by ingestion or inhalation. Not one out of the large number of organic pigments which have thus been tested has demonstrated any irreversible toxic effect. No toxic response was observed in rats which were fed either Pigment Yellow 1 or Pigment Yellow 57 1 for 30 days [22],... 

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). 

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