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).