Subacute toxicity tests

Hill, E.F. and M.B. Camardese. 1982. Subacute toxicity testing with young birds response in relation to age and intertest variability of LC50 estimates. Pages 41-65 in D.W. Lamb, and E.E. Kenaga (eds.). Avian and Mammalian Wildlife Toxicology Second Conference. Am. Soc. Testing Mater. ASTM STP 757. 

Chronic toxicity Rodent and nonrodent species for > 6 months. Required when drug is intended to be used in humans for prolonged periods. Usually run concurrently with clinical trials. Determine same end points as subacute toxicity tests. 

In a 12-week, subacute toxicity test in rats given intraperitoneal injections of epichlorohydrin, treatment led to a dose-related decrease in haemoglobin values an increase in segmented neutrophils was seen with doses of 56 mg/kg bw and a reduction in the proportion of lymphocytes occurred at doses of 22 and 56 mg/kg bw (Lawrence et al., 1972). An increased leukocyte count was observed in animals exposed chronically to vapours of epichlorohydrin in air at concentrations of 2 mg/m (Fomin, 1966). The maximum tolerated dose in a 13-week subacute study in rats following oral administration of epichlorohydrin was 45 mg/kg bw per day (Oser et al., 1975). 

Table VI. Subacute Toxicity Tests Required for Registration (Technical and Formulations)...

Komiyama, BC, Y. Kawakubo, T. Fukushima, et al. 1977. Acute and subacute toxicity test on the extract from Glycyrrhiza. Oyo Yakuri 14(4) 535-548. Cited in Isbrucker, R.A., and G.A. Burdock. 2006. Risk and safety assessment on the consumption of Licorice root (Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyr-rhizin. Regul. Toxicol. Pharmacol. 46(3) 167-192. 

Chronic toxicity tests determine the effects of either single or multiple exposures to medical devices, materials, and/or their extracts during a period of at least 10% of the life span of the test animal, for example, over 90 days in rats. Chronic toxicity tests may be considered an extension of subchronic (subacute) toxicity testing and both may be evaluated in an appropriate experimental protocol or study. 

Ino, N. Tanaka, T. Okumura, A. Morishita, Y. Makita, H. Kato, Y. Nakamura, M. Mori, H. Acute and subacute toxicity tests of madder root, natural colorant extracted from madder (Rubia tinctorium), in (C57BL/6 X C3H)F1 mice. Toxicol. Ind. Health 1995,11,449-458. 

The health effects of sorbic acid and sorbates have been reviewed (165—167). The extremely low toxicity of sorbic acid enhances its desirabiHty as a food preservative. The oral LD q for sorbic acid in rats is 7—10 g/kg body weight compared to 5 g/kg for sodium chloride (165—169). In subacute and chronic toxicity tests in rats, 5% sorbic acid in the diet results in no abnormal effects after 90 days or lifetime feeding studies. A level of 10% in rat diets results in a slight enlargement of the Hver, kidneys, and thyroid gland (170). This same dietary level fed to mice also resulted in an increase in Hver and kidney weight... 

Physicochemical properties requked include melting/boiling point, vapor pressure, solubiUty, and flammabiUty/explosion characteristics. The toxicological studies include acute toxicity tests, oral, inhalation, and dermal skin and eye kritation skin sensiti2ation subacute toxicity, oral, inhalation, and dermal and mutagenicity tests. In vitro reverse mutation assay (Ames test) on Salmonella typhimurium and/or E.scherichia coli and mammalian cytogenic test. In vivo mouse micronucleus test. 

For disodium undecyleneamido MEA-sulfosuccinate (DUMS) a test report [97] indicates that the subacute toxicity, measured as 30% of LD50 during 5 days, allowed all test animals to survive. 

Ecotoxicological Prolonged fish toxicity (including reproduction) Avian acute/subacute toxicity Accumulation, degradation and mobility tests... 

In toxicity studies, acute toxicity tests are usually carried out in the rat, mouse, cat, and dog. Subacute toxicity studies for IM products are performed by giving SC injections to rats and IM injections to dogs. In IV studies the rat tail vein or a front leg is used. Deliberate overdosing usually washes out metabolism differences between species. In dogs it is common to give an IV dose five times that intended for humans. In rats this is increased to 10 times. 

Major organ function tests Acute and subacute toxicity studies... 

Toxicological properties Acute toxicity (by two routes of admission) Skin irritation Eye irritation Skin sensitization 28 days subacute toxicity Ames test In vitro metaphase analysis (or mouse micronucleus test)... 

Oral toxicity. The approximate lethal dose of the dicyclo-hexyl-18-crown-6 polyether for ingestion by rats was 300 mg./ kg. In a 10-day subacute oral test, the compound did not exhibit any cumulative oral toxicity when administered to male rats at a dose level of 60 mg./kg./day. It should be noted that dosage at the approximate lethal dose level caused death in 11 minutes, but that a dose of 200 mg./kg. was not lethal in 14 days. 

Tansy MF, Werley M, Landin W Subacute inhalation toxicity testing with iodoform vapor. Toxicol Environ Health 8 59-70, 1981... 

Reddy, J.K., Moody, D.E., Azamoff, D.L. Rao, M.S. (1976) Di-(2-ethylhexyl)phthalate an industrial plasticizer induces hypolipidemia and enhances hepatic catalase and carnitine acetyltransferase activities in rat and mice. Life Sci., 18, 941-945 Reddy, J.K., Reddy, M.K., Usman, M L, Lalwani, N.D. Rao, M S. (1986) Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drag. Environ. Health Perspect., 65, 317-327 Rexroat, M.A. Probst, GS. (1985) Mutation tests with Salmonella using the plate-incorporation assay. Prog. Mutat. Res., 5, 201-212 Rhodes, C., Orton, T.C., Pratt, I.S., Batten, P.L., Bratt, H., Jackson, S.J. Elcombe, C.R. (1986) Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets extrapolation of effects in rodents to man. Environ. Health Perspect., 65, 299-307... 

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