Subchronic tests, duration

The database for HFC-134a is extensive it contains studies with both human subjects and animal models. Potentially sensitive populations, including patients with COPD and adult and pediatric asthmatic patients, were tested with direct inhalation of HFC-134a from metered-dose inhalers. The response of these groups was no different than that of healthy adults. The 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 metabolism of HFC-134a is well understood, and the relationship of exposure con... 

The 28-day smdies are termed repeated dose (28 days) while the 90-day smdies are termed subchronic. The chronic toxicity test (B.30), requests at least 12 months duration. The preferred species is the rat. 

Woutersen et al. (1985, as cited in Kalberlah and Schneider 1998 ECETOC 1995, 2003) evaluated toxicity data relating to 82 substances including stabilizers, plasticizers, antioxidants, disinfectants, food additives, pesticides, other agrochemicals, and industrial chemicals. The substances were each tested (oral administration to rats) for a subacute (2-4 weeks) and a subchronic (13-18 weeks) duration of exposure. Both the NOAEL and the LOAEL were included in the comparison. For 56% of the substances (46), the ratio NOAELsubacute/ NOAELsubchronic was about 1. For 44% of the substances (36), the subchronic NOAEL was lower than the subacute NOAEL (i.e., the ratio was above 1), and for 3/82 substances, the ratio was above 100. The 95th percentile was about 10. A factor of 4 covered 70%-80% of the substances. 

Subacute or subchronic toxicity Three doses, two species. 2 weeks to 3 months of testing may be necessary before clinical trial. The longer the duration of expected clinical use, the longer the subacute test. Determine biochemical, physiologic effects. 

In the subchronic neurotoxicity study, end points measured are similar to those measured in the acute neurotoxicity study. However, the duration of dosing is 90 days and exposure to the test material is usually via the diet. As for the acute neurotoxicity study, these studies consist of three test groups and a control group. The functional observation battery and motor activity tests are conducted at selected intervals such as weeks 5, 9, and 13, as well as pretest. At test termination, at least 6 animals per group are perfused via the heart with fixative to ensure optimal fixation of nervous tissues for histopathology examination. Nervous tissues examined include brain, spinal cord (various segments), and selected nerves such as the optic, sciatic, tibial, and sural nerves. 

The subchronic inhalation toxicity should be studied with at least three concentrations of the test chemical with a control (and where appropriate, a vehicle control corresponding to the concentration of the vehicle at the highest exposure level). The remaining details of exposure are similar to those described for acute oral and acute inhalation toxicity. The duration of daily exposure should be 6 hours after equilibrium of the chamber concentrations. Other durations may be used to meet specific requirements. 

Test compounds can cause both local and systemic adverse effects local effects occur at the sites of initial contact (e.g., injection sites), while systemic effects are observed in organs remote from the site of initial exposure. The degree of toxicity is dependent on the number of exposures or the duration. Effects can be classified as acute (i.e., short term following a single dose) repeated or multiple exposure effects can be referred to as short term (not more than 5% of life span), subchronic (5-20% of life span), and chronic (the entire or a major part of life span). 

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