TECNAZENE JMPR 1974 Explanation Tecnazene (1,2,4,5-tetrachloro-3-nitrobenzene, 2,3,5,6-tetra- chloronitrobenzene, TCNB) was scheduled for evaluation by the present Meeting, but insufficient data on which to base recommendations were received. The limited information available to the Meeting is reviewed below. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, distribution and excretion Following oral administration to rabbits at doses ranging from 0.1 to 3 gm/animal, the major quantity of material was rapidly excreted in the faeces (60-78%) within three days. Quantities were observed in the urine (35-38%) primarily as conjugated products. At lower doses, 22-30% of a single oral dose was recovered in the faeces (Bray et al., 1953). Biotransformation Following oral administration to rabbits, isolation and identification of metabolites indicated that reduction (predominantly bacterial) of the nitro group took place in the gut. Very small amounts of pentachloroaniline, a mercapturic acid derivative, 4-amino-2,3,5,6-tetrachlorophenol, a sulphate, and a glucuronide were excreted in the urine (Menzie, 1969; Bray et al., 1951; 1952; 1953). Reduction of the nitro group to the aniline derivative was observed in vitro with rat liver preparations incubated with tecnazene for three hours (Bray et al., 1953). TOXICOLOGICAL STUDIES Acute Toxicity The acute oral LD50 in the rat was approximately 7 500 mg/kg bw (Klimmer, 1971). No untoward reactions or signs or irritation were observed following installation of tecnazene, directly in the conjunctival sac of rabbits. No toxic effects were observed after tecnazene was applied to the shaved backs of rabbits for two successive days. Dermal blackening and induration were observed after six days. A dose of 500 mg applied to the skin caused slight discoloration but no induration (Buttle & Dyer, 1950). Repeated oral administration of tecnazene (3 gm) to adult female rabbits resulted in no apparent adverse effects. The administration of an isomer (2,3,4,5-tetrachloronitrobenzene) administered in doses of 700 mg/rabbit produced a slight anorexia persisting up to two days. Repeated doses of 2,3,5,6-tetrachloroaniline (1 gm/rabbit) did not result in any adverse effects (Bray et al., 1953). Short Term Studies Mouse A group of 24 mice were fed tecnazene (13.68%) in the diet, consuming 250 mg/day (10 000 mg/kg body weight/day). Mortality was observed in 3-4 days and this test was discontinued. Fatty degeneration of the liver and fatty changes in the spleen and kidney were noted (Buttle & Dyer, 1950). Groups of mice (12 mice/group) were fed tecnazene in the diet at levels of 0, 1 344, and 13 440 ppm for 31 days. Growth was inhibited at the high level. Growth was normal and no adverse effects were observed at 1344 ppm (equivalent to 134 mg/kg body weight/day) (Buttle & Dyer, 1950). Rat Groups of rats (5 males and 5 females per group) were fed tecnazene in the diet for ten weeks at levels of 0, 800, 4000, and 20 000 ppm. Mortality was noted at the high dose. Growth was reduced at 4000 ppm. No effects were noted on growth or mortality at 800 ppm, (Buttle & Dyer, 1950). Groups of rats (5 males and 5 females per group) were fed tecnazene at levels of 0, 200, 800, and 3200 ppm in the diet for twelve weeks and mated to produce an F1 generation. Five rats of each sex of the F1 generation were maintained after weaning on the respective diets for a further twelve weeks and mated to produce an F2 generation. Growth was slightly inhibited at the 3200 ppm dose level over the twelve week measurement interval in each generation. Fatty infiltration of the liver was also observed at 3200 ppm. No effects were noted at 800 ppm in any of the animals examined (Buttle, 1974). Dog Groups of dogs (2 males and 2 females per group; controls - 1 male and 1 female) were treated with tecnazene orally by capsule for two years at levels of 0, 3.75, 15, 60, and 240 mg/kg body weight/day (6 days/week). Mortality was observed at the high level and all animals died within the first year of the study. Growth was normal in all animals at 60 mg/kg. Clinical chemistry was normal at 15 mg/kg. The values for serum alkaline phosphatase activity were elevated at 60 and 240 mg/kg. Microscopic changes were observed in liver, kidney, and bone marrow at the high feeding level. No effects attributed to the administration of tecnazene were noted in haematological and urological values or in measurement of EKG (Donikian et al., 1965). Long Term Studies Rat Groups of rats (20 males and 20 females per group) were fed tecnazene in the diet for two years at levels of 0, 25, 100, 400, and 1600 ppm. No significant effects were noted on growth, food consumption, clinical chemistry, haematology, or by gross and microscopic examination of tissues and organs. Survival of rats over the 104 day duration of the experiment was poor. In the control groups, only 2/20 males and 5/20 females lived to complete the study. No males were alive at the two highest doses at 104 weeks. Clinical chemistry values (SGPT, SGOT, etc.), determined only at 104 weeks, were normal in all surviving animals. As there were no animals that survived at the high doses, those parameters which were reduced in the dog study could not be evaluated (Owen et al., 1965). Observations in man Occupational dermal sensitivity in man has been reported in agricultural workers (Lupuknova, 1965). Comments Tecnazene, one of several polychlorinated nitrobenzene isomers is rapidly absorbed and metabolized although the metabolic fate in mammals is not well defined. High doses of tecnazene are predominantly passed unchanged in the faeces. In mice, growth was inhibited at a dietary level of 13 440 ppm with no effects noted at 1 344 ppm, over a 31 day interval. Dietary administration to rats at a dose equivalent to 400 mg/kg resulted in a growth reduction while 1 111 mg/kg was fatal within three weeks. In a long term study in rats, no effects were noted at 1 600 ppm in the diet although few animals survived to the end of the study. In dogs no effects were noted in a two-year study at 15 mg/kg. Slight effects in dogs were noted as an increased serum alkaline phosphatase at higher doses. No evidence of tumorgenicity was noted in the rat study. However, a complete evaluation of this study was difficult as survival was poor up to two years. Data from adequate research protocols supporting the safety of pesticides in food are not available with this compound. No studies are available relating to mutagenicity, teratogenicity, effects on reproduction, metabolism in mammals other than the rabbit, mechanism of action, or the effects on man. In the absence of significant data the Meeting was unable to allocate an ADI for man. TOXICOLOGICAL EVALUATION No ADI allocated. RESIDUES IN FOOD AND THEIR EVALUATION Explanatory note Tecnazene was developed prior to 1940 for fungicidal uses and has been introduced for the control of Botrytis and Sclerotina in vegetables, Fusarium (dry rot) in potato growing and as a sprout inhibitor on stored potatoes. Registrations of 3-5% dusts and of smoke preparations have been recorded for a few countries, e.g. New Zealand, USA and the Netherlands. Some of these registrations have been phased out in later years, but at the same time renewed interest in the chemical has been reported, especially for some greenhouse cultures. Apart from some early residue data on the uptake of tecnazene in potatoes and its fate during their storage and cooking, no further information has been made available to the Meeting. Under the circumstances no recommendations for residue limits could be made before full information on chemical and formulated products specifications (including impurities, e.g. HCB), present use patterns, residue data from supervised trials, fate of residues in crops other than potatoes and in soils etc. is made available. Considering the lack of information, including the uncertainties concerning the present uses of the compound, the Meeting was unable to review the needs for further evaluation of tecnazene. It was agreed that the need for further work should be considered by the Codex Committee on Pesticide Residues. FURTHER WORK OR INFORMATION REQUIRED (if further evaluation is to be undertaken) 1. Adequate toxicological data. 2. Full information on specifications for the chemical and the formulated products (including impurities, e.g., HCB), present use patterns, residue data from supervised trials, rate of residues in crops other than potatoes and in soils, etc. REFERENCES Bray, H.G., Hybs, Z., Lake, H.J. and Thorpe, W.V. (1951) The metabolism of 2,3,5,6-tetrachloronitrobenzene and 2,3,4,5-tetrachloronitrobenzene in the rabbit. Biochem. J., 49:lxv. Bray, H.G., Hybs, Z., James, S.P. and Thorpe, W.V. (1952) The formation of mercapturic acid from 2,3,5,6-tetrachloronitrobenzene in the rabbit. Biochem. J., 52:xviii. Bray, H.G., Hybs, A., James, S.P. and Thorpe, W.V. (1953) The metabolism of 2,3,5,6- and 2,3,4,5-tetrachloronitrobenzenes in the rabbit and the reduction of aromatic nitro compounds in the intestine. Biochem. J., 53:266-273. Buttle, G.A.H. (1974) Experiments on the chronic toxicity of 2,3,5,6-tetrachloronitrobenzene administered to rats over three generations. Report submitted by Sterwin Chemicals, Inc. to F.D.A. (Unpublished). Buttle, G.A.H. and Dyer, F.J. (1950) Experiments on the toxicology of 2,3,5,6-tetrachloronitrobenzene. J. Pharm. Pharmacol., 2:371-375. Donikian, M., Owen, S.D., Wiland, J. and Drobeck, H.P. (1965) Oral administration of 2,3,5,6-tetrachloronitrobenzene to beagle dogs for two years. Report from Sterling Winthrop Research Institute. (Unpublished). Klimmer, O.R. (1971) Pflanzenschutz und Schädlings - bekämpfungsmittel. Abriss liner Toxicologie und Therapie von Vergiftungen. Pub. Hundt-Verlag. p. 78. Lupuknova, K.A. (1965) Case of occupational toxicodermia caused by 2,3,5,6-tetrachloronitrobenzene. Gigiena Truda i Prof. Zabolevaniya, 9:56-58. (In Russian) (Chem. Abs. 63:12219h, 1965). Menzie, C.M. (1969) Metabolism of Pesticides. U.S. Dept. Interior. Special Scientific Report. Wildlife No. 127:302. Owen, S.D., Fabian, R., Donikian, W.J. and Drobeck, H.P. (1965) Oral administration of 2,3,5,6-tetrachloronitrobenzene in the diet to albino rats for two years. Report from Sterling Winthrop Research Institute. (Unpublished).
See Also: Toxicological Abbreviations Tecnazene (EHC 42, 1984) Tecnazene (HSG 12, 1988) Tecnazene (Pesticide residues in food: 1978 evaluations) Tecnazene (Pesticide residues in food: 1981 evaluations) Tecnazene (Pesticide residues in food: 1994 evaluations Part II Toxicology)