Subchronic toxicity study

Daly, IW. 1989. A 13-week subchronic toxicity study of methyl parathion in dogs via the diet followed by a one-month recovery period. Stilwell, KS Mobay Corporation. 

Tansy MF, Kendall FM, Fantasia J, et al. 1981. Acute and subchronic toxicity studies of rats exposed to vapors of methyl mercaptan and other reduced-sulfur compounds. J Toxicol Environ Health 8 71-88. 

Payne, J.F., J. Kiceniuk, L.L. Fancey, U. Williams, G.L. Fletcher, A. Rahimtula, and B. Fowler. 1988. What is a safe level of polycyclic aromatic hydrocarbons for fish subchronic toxicity study on winter flounder (Pseudopleuronectes americanus). Canad. Jour. Fish. Aquat. Sci. 45 1983-1993. 

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). 

Pharmacokinetics and Metabolism. Pharmaceutical subchronic toxicity studies are always accompanied by a parallel determination of the pharmacokinetics of the material of interest administered by the same route as that used in the safety study. 

Dose selection is one of the most important activities in the design of a toxicology study. It is especially critical in carcinogenicity studies because of their long duration. Whereas faulty dose selection in an acute or subchronic toxicity study can easily be corrected by repeating the study, this situation is much less desirable in... 

The information used for dose selection usually comes from subchronic toxicity studies, but other information about the pharmacological effects of a drug and its metabolism and pharmacokinetics may also be considered. The maximum recommended human dose (MRHD) of the drug may be an additional criterion, if this is known when the carcinogenicity studies are being designed. 

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],... 

Subchronic Toxicity Studies of Aqueous Extract of Alangium salvifolium Leaves in Rats... 

Guzman, A., Garcia, C., and Demestre, I. Acute and subchronic toxicity studies of the new quinoline antibacterial agent irloxacin in rodents, Arzneim. Forsch., 49(5) 448-456, 1999. 

Lindamood C, Farnell DR, Giles HD, et al Subchronic toxicity studies of r-butyl alcohol in rats and mice. Fundam Appl Toxicol 19 91-100, 1992... 

Schilling K, Kayser M, Deckardt K, et al Subchronic toxicity studies of 3-methyl-1-butanol and 2-methyl-1-propanol in rats. Hum Exp Toxicol 16(12) 722-6, 1997... 

Tompkins EC Rat oral subchronic toxicity study. Compound isobutyl alcohol. Govt Reports and Announcements Index (GRA I), Issue 11, 1988... 

Daniel FB, Condie LW, Robinson M, et al. 1990. Comparative subchronic toxicity studies of three disinfectants. J Am Waterworks Assoc, 61-69. 

Hayes JR, Condie LW, Borzelleca JF. 1986. Acute, 14-day repeated dosing, and 90-day subchronic toxicity studies of carbon tetrachloride in CD-I mice. Fund AppI Toxicol 7 454-463. 

Janer G, Hakkert BC, Piersma AH et al (2007) A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reprod Toxicol 24(1) 103-113... 

DeMerlis CC, Schoneker DR, Borzelleca JF. A subchronic toxicity study in rats and geno-toxicity tests with an aqueous ethylcellulose dispersion. Food Chem Tox 2005 43 1355. 

Battelle. Subchronic toxicity study Naphthalene (C52904), Fischer 344 rats. Report to US Department of Health and Human Services, National Toxicology Program, Research Triangle Park, NC, by Battelle Columbus Laboratories, Columbus, OH, 1980. 

TABLE 2-10 Exposure Period in a Repeated-Dose and Subchronic Toxicity Study... 

In the subchronic toxicity study, if interim sacrifices are planned, the number of animals should be increased so that there is no shortage of animals at the termination of the study this ensures meaningful conclusions about the test chemical s toxicity. In addition, a satellite group of 20 animals (10 of each gender) may be treated with the high dose of the test chemical for 90 days. These animals should be observed for signs of adverse effects, (e.g., reversibility, persistence, delayed occurrence of toxic effects). The observation period should last for a posttreatment period of appropriate length not less than 28 days. 

Hazleton. 1989. Subchronic toxicity study in rats with paranitrophenol (HLA, study no. 241-221). Sponsored by Monsanto Co., St. Louis, Mo. NTIS/OTS0526338. 

The FDA and most other regulatory agencies require subchronic toxicity studies in two species, one of which is a nonrodent, before human clinical trials are initiated. The recommended duration of the subchronic toxicity studies is related to duration of the proposed clinical trials. An ICH Guideline (8) suggests the minimum duration of toxicity studies, shown in Table 2, needed to support phase 1, 2, and 3 clinical trials in which humans are to be exposed to the drug candidate for varying durations. 

In the risk assessment, some steps are not well described. For example, subchronic toxicity studies and not chronic toxicity studies are used in the risk assessment. Exposure duration and frequency considerations are not discussed. Route-to-route extrapolation is considered acceptable implicitly, without further evaluation of the various issues involved. The rationale for using a dermal absorption default of 10 %, in the absence of data is also not discussed. 

Truelove, J., Mueller, R., Pulido, O., and Iverson, F. 1996. Subchronic toxicity study of domoic acid in the rat. Food Chem Toxicol 34, 525-529. 

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