NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.
Prepared by: Mary Lou Daugherty, M.S., Chemical Hazard Evaluation and Communication, Group, Biomedical and Environmental Information Analysis Section, Health and Safety, Research Division, *.
Prepared for: Oak Ridge Reservation Environmental Restoration Program.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.
Trinitrophenylmethylnitramine (tetryl) is a monoclinic crystalline solid that is used as a intermediary detonating agent for less sensitive high explosives and as a booster charge in certain military munitions. Although contact with tetryl-laden dust is the primary source of human occupational exposure, nonoccupational exposure can potentially occur through contact with contaminated surface waters, soils, sediments and ground water.
Human studies that describe the rate of tetryl absorption, distribution, metabolism and excretion were not identified in the available literature. A study conducted using rabbits indicates that tetryl is poorly absorbed from the gastrointestinal tract and slowly metabolized (Zambrano and Mandovano, 1956). Studies that identified the distribution of tetryl following absorption and elimination other than in the urine were not identified. Another study determined that gavage treatment of male rabbits with tetryl for 9 months induced renal and hepatic degenerative effects (Fati and Daniele, 1965). On the basis of these effects, a lowest-observed-adverse-effect-level (LOAEL) of 125 mg/kg/day for tetryl was derived. Based on the LOAEL, a subchronic reference dose (RfDs) of 100 µg/kg and a chronic reference dose (RfD) of 10 µg/kg were calculated. Data are presently insufficient to derive a reference concentration (RfC) for tetryl.
The primary target organ of tetryl toxicity is the skin. Human occupational exposure to tetryl induces a compound-related dermatitis. The dermatitis is characterized by erythema, particularly on the neck, chest, back and the inside surface of the forearms. The erythema can lead to localized desquamation in affected areas. There is some indication that the dermatitis on occasion may involve an allergic response. Other target organs of tetryl toxicity include the upper respiratory tract, kidney, liver and central nervous system. Female workers at munition facilities have developed menstrual disorders following exposure to tetryl (Cripps, 1917).
No information is available concerning the developmental toxicity of tetryl to humans or animals. No suitable cancer bioassays or epidemiological studies are available to assess the carcinogenicity of tetryl. Therefore, U.S. EPA (1990) has placed tetryl in weight-of-evidence group D, not classifiable to human carcinogenicity.
Trinitrophenylmethylnitramine (CAS No. 479-45-8) is also known by the synonyms picrylmethylnitramine, tetralite, nitramine, N,2,4,5-tetranitro-N-methylaniline, 2,4,6-trinitrophenyl-N-methylnitramine, and the synonym that will be used for the remainder of this report, tetryl (Sittig, 1981). Tetryl is a Class A explosive that is used as an intermediary detonating agent for less sensitive high explosives and as a booster charge in certain military munitions. Tetryl has a molecular weight of 287 and a specific gravity of 1.57 (Windholz et al., 1983). Synthesized by the sulfation of N,N-dimethylaniline in concentrated sulfuric acid followed by nitration in concentrated nitric acid, tetryl is a yellow monoclinic crystalline solid with a melting point of 130C. Tetryl is only slightly soluble in water (7.5 mg/L) but is soluble in 95% alcohol, chloroform, nitric acid, benzene, glacial acetic acid, and ether (Kaye and Herman, 1980; ITII, 1986). A powerful oxidant and a dangerous fire hazard sensitive to shock and friction, tetryl explodes at 187C and on contact with trioxygen difluoride. Tetryl will ignite when exposed to hydrazine and emit toxic fumes of nitrous and nitric oxide when heated to decomposition (Sax and Lewis, 1989).
Because significant concentrations of tetryl dust arise from booster charge manufacture and subsequent munitions handling processes (Parmeggiani, 1983), human occupational exposure occurs through dermal contact and by oral and inhalation routes. Airborne tetryl exists primarily as a particulate that is subject to physical removal by wet and dry deposition. Tetryl has been detected in the wastewater effluents of several production and munition facilities. Therefore, the potential exists for the nonoccupational exposure to tetryl from not only the contamination of surface waters, soils, and sediments but also ground water supplies (U.S. EPA, 1990).
Specific information on absorption following exposure to tetryl was not identified in the available literature. However, anemia and gastrointestinal effects in humans and mild renal, hepatic and splenic effects in rabbits, rats, and dogs following tetryl exposure provides indirect evidence of absorption. Zambrano and Mandovano (1956) reported that tetryl absorption was poor in rabbits treated by gavage with a cumulative dose of 1 g. Although other routes of excretion were not investigated, the authors based their conclusion on the presence of the tetryl metabolite picramic acid in the urine. This metabolite, however, was not detected until several days after treatment. Sittig (1985) did not provide specific information, but has reported tetryl can be absorbed through the skin.
Information regarding the distribution of tetryl following absorption was not identified in the available literature. However, adverse effects observed in the liver, kidney and spleen of experimentally exposed laboratory animals indicate that tetryl (or a metabolite) may have been distributed to these organs.
Zambrano and Mandovano (1956) studied the urinary metabolic products of seven rabbits treated by gavage with the equivalent of 36 mg tetryl/kg/day for 30 days. Although picric acid was not detected, picramic acid (2-amino-4,6-dinitrophenol) and its sulfate conjugate were detected once the cumulative tetryl dose reached 1 g. The authors theorized that picramic acid and its conjugate were derived from the oxidation of tetryl to picric acid (2,4,6-trinitrophenol) with subsequent nitro-reduction to form picramic acid. Information on metabolism and metabolic products formed in other species was not identified in the available literature.
The qualitative detection of picramic acid and its sulfate conjugate in the urine of rabbits treated with tetryl indicates that this is one route of tetryl excretion (Zambrano and Mandovano, 1956). However, quantitative data regarding the rate of tetryl excretion in the urine, as well as the contribution of other routes of excretion, were not identified in the available literature.
Human occupational exposure to tetryl produces various toxic effects. Because occupational exposure occurs in areas that have high atmospheric concentrations of tetryl-laden dust, it is likely that a combination of oral exposure from the swallowing of dust impacted on the pharynx or from mucocilliary transport, inhalation exposure, and dermal exposure result in the observed tetryl-related toxic effects. Therefore, it is not possible to attribute all tetryl-related effects to specific exposure routes.
Specific information on the acute oral toxicity of tetryl to humans was not available.
Parmeggiani et al. (1956) reported on the oral toxicity of tetryl to rats (age, sex, number, and strain were not reported). Rats that received 0.25 g/kg of tetryl for 15 days developed degenerative renal lesions. No apparent toxicity was observed in rats treated with a single dose of 1 g/kg of tetryl, but rats that received 1 g/kg tetryl for 3 days developed degenerative renal lesions. Rats that received 1 g/kg tetryl for 10-14 days developed renal tubular epithelium alterations and had increased mortality. After treatment with a single 2 g/kg tetryl dose, the rats developed hepatic proliferative effects, renal tubular hypertrophy, and splenic atrophy with hemosiderosis.
Wells et al. (1920) reported that rabbits treated by gavage with 1 g/kg tetryl died after 1-3 doses. Microscopically, the renal tissue of the rabbits contained swollen epithelia and focal areas of convoluted tubular necrosis.
Parmeggiani (1983) reported that subchronic occupational exposure to tetryl can result in various digestive disorders such as loss of appetite, abdominal pain, vomiting, and loss of weight. In addition, tetryl exposure can induce diffuse central nervous system effects such as headaches, insomnia, exaggerated reflexes, mental excitation, malaise and fatigue. Other effects observed after oral tetryl exposure include chronic hepatitis, leucocytosis and a slight anemia (Parmeggiani, 1983; Sittig, 1985).
Daniele (1964) reported the effect of oral tetryl treatment on the blood coagulation cascade of rabbits. Twelve rabbits (age and sex not specified) were given 125 mg/kg/day of tetryl by gavage for 6 months. After 3 months of tetryl treatment, the coagulation indices were not affected, but after 6 months, decreased blood coagulability was observed in treated rabbits when compared to control rabbits.
Fati and Daniele (1965) reported on the histopathological effects to certain organs following oral tetryl treatment. Twelve male rabbits (strain not specified) were treated daily by gavage with 125 mg/kg of tetryl. After 6 and 9 months, three and nine rabbits, respectively, were sacrificed and the liver, kidney, heart, lungs and intestinal mucosa were examined microscopically for tetryl-related signs of toxicity. After 6 months of tetryl treatment, hepatic hypertrophy as well as splenic effects of congestion, capsula thickening, lymphatic follicular atrophy and hemosiderosis were noted. After 9 months of treatment, circumscribed focal areas of hepatic necrosis, as well as vascular congestion and hyperplastic Kupffer cells were observed. Essentially unaffected after 6 months of treatment, the kidney contained areas of mild congestion, areas of turbid swelling and vacuolar degeneration, and regions of swollen renal cells containing opaque, granular or vacuolized protoplasm after 9 months of treatment. No tetryl-related treatment effects were seen in the heart, lungs or intestinal mucosa.
Zambrano and Mandovano (1956) treated seven rabbits (age, sex and strain not specified) with 100 mg/rabbit/day (approximately 36 mg/kg/day) of tetryl for >30 days. The only treatment-related effect reported was a decrease in body weight, however, statistical analysis was not done. No other treatment-related endpoints of tetryl toxicity were examined.
Specific information on the chronic oral toxicity of tetryl to humans and animals was not available.
Information on the developmental of tetryl to humans or animals following oral exposure was not available. Cripps (1917) reported that the menstrual cycle of female munition workers was disrupted following exposure to tetryl. The menstrual disturbances included increased duration and flow and were of decreased frequency.
ORAL RfDs: 100 µg/kg/day
UNCERTAINTY FACTOR: 1000
MODIFYING FACTOR: 1
LOAEL: 125 mg/kg/day
Data Base: Low
VERIFICATION DATE: Not verified
PRINCIPAL STUDY: Fati and Daniele, 1965
COMMENTS: The RfD value is based upon a weight-of-evidence approach using a subchronic rabbit oral gavage study. The Uncertainty Factor of 1000 is the product of uncertainties allowing for: extrapolation of the dose levels from laboratory animals to humans (10), threshold for sensitive humans (10), and extrapolation from a LOAEL to a NOAEL (10). Confidence in the study is rated low because only one dose level was tested and endpoints other than histology of selected organs were not examined. Confidence in the data base is rated low because only one species (rabbits) was studied, as well as the lack of chronic, reproductive and other specialized data. There was sufficient indication in the study report to suggest that effects to the body weight may occur with doses below the LOAEL (U.S. EPA, 1990).
ORAL RfD: 10 µg/kg/day
UNCERTAINTY FACTOR: 10,000
MODIFYING FACTOR: 1
LOAEL: 125 mg/kg/day
Data Base: Low
VERIFICATION DATE: Not verified
PRINCIPAL STUDY: Fati and Daniele, 1965
COMMENTS: The RfD value is based upon a weight-of-evidence approach using a subchronic rabbit oral gavage study. The Uncertainty Factor of 10,000 is the product of uncertainties allowing for: extrapolation of the dose levels from laboratory animals to humans (10), threshold for sensitive humans (10), extrapolation from a LOAEL to a NOAEL (10), and extrapolation from subchronic to chronic (10). Confidence in the study is rated low because only one dose level was tested and endpoints other than the histology of selected organs were not examined. Confidence in the data base is rated low because only one species (rabbits) was studied, as well as the lack of chronic, reproductive and other specialized data. There was sufficient indication in the study report to suggest that effects to the body weight may occur with doses below the LOAEL (U.S. EPA, 1990).
Parmeggiani (1983) reported that exposure to tetryl produces an acute irritation of the nasal and pharyngeal mucous membranes, presumably due to the irritant effects of tetryl crystals. He also stated that due to their large size, tetryl crystals do not usually reach the bronchi, but instead induce an upper respiratory tract irritation that results in a dry cough and bronchial spasms. Workers exposed to high concentrations of tetryl for 3-4 days often complained of headaches and nosebleeds.
Information on the subchronic inhalation toxicity of tetryl to humans available.
Information on the subchronic inhalation toxicity of tetryl to animals was not available.
Information on the chronic inhalation toxicity of tetryl to humans or animals was not available.
Information on the developmental and reproductive inhalation toxicity of tetryl to humans or animals was not available.
Pertinent information for deriving a reference concentration (RfC) for tetryl following subchronic or chronic exposure is not available at this time.
Within a few days of tetryl exposure, a yellowish discoloration of the hands, face, scalp and hair is frequently observed. This indicator of tetryl exposure is usually accompanied by conjunctivitis and palpebral and periorbital edema (Parmeggiani, 1983).
Wells (1920) studied the acute toxicity of tetryl dissolved in olive oil given by subcutaneous injection to dogs. Five daily doses of 100 mg tetryl/kg resulted in the death of a dog on day 15. A single subcutaneous dose of 2.5 g/kg to a dog was not lethal, but a 5 g/kg dose resulted in death within 18 hours. These results yield an LDLo of 5000 mg/kg. Acute inflammation, edema and hemorrhage, as well as a "waxy" degeneration of the underlying musculature were observed at the subcutaneous tetryl injection sites. Microscopic examination of the kidneys showed toxic degeneration and necrosis of the convoluted tubules with the presence of fat granules within the epithelium of the Loop of Henle. The liver of tetryl-treated dogs contained areas of centrilobular necrosis along with fatty degeneration of the hepatocytes.
Occupational exposure during munitions processing has been reported to cause a tetryl-induced dermatitis. Witkowski et al. (1942) reported that 1150 of 5000 munition workers developed toxic reactions to tetryl. Of the affected workers, 75% had developed a "trinitrophenylmethyl-nitramine dermatitis". The dermatitis, typically appearing 2-3 weeks after exposure, was characterized by erythema, particularly on the neck, chest, back and the inside surface of the forearms. After a few days, the erythema regressed and left areas of moderate desquamation. Workers who continued to work in areas of high tetryl concentrations, despite the development of dermatitis, often developed a tolerance to tetryl (Parmeggiani, 1983).
Goh (1984) conducted a case study on an otherwise healthy female of 37 years who developed allergic dermatitis after working in a munitions facility. Four months after beginning work, the female developed symptoms of swelling and yellowish discoloration of the fingers and hands, swelling of the lips and a rash on the neck. Hematological parameters as well as serum carotene and liver function tests were normal. Initial patch tests were positive for trinitrotoluene (TNT) and negative for tetryl and cyclotrimethylenetrinitramine (RDX). However, the individuals' symptoms did not improve following removal from sources of TNT exposure and were exacerbated upon re-exposure to tetryl and RDX. The author concluded after repeat patch testing, that the individual was sensitized to tetryl and not to the structurally similar TNT. The removal of the female from sources of TNT and tetryl exposure improved her symptomology.
Allergic dermatitis has been produced in laboratory animals after exposure to tetryl. Gell (1944) exposed four male and four female guinea pigs (strain not specified) to a "smoke", generated by blowing compressed air through a 10% solution of tetryl in acetone into exposure chambers. The guinea pigs were exposed for six 30-minute periods during a 14-day period. Gell (1944) estimated that average particle size of tetryl was 2-3 µm, that the animals were exposed to an atmospheric concentration of approximately 0.4 mg/L, and, during the study period, "absorbed" a cumulative dose of 7-10 mg of tetryl. The actual dose the guinea pigs absorbed, however, can not be determined because of the manner of tetryl treatment. The guinea pigs were exposed to tetryl in "whole body chambers", and therefore exposure to tetryl would have included not only inhalation exposure, but also oral and dermal exposure. The results are significant, however, for demonstrating allergic dermatitis in 1/8 guinea pigs and an anaphylactic sensitivity in 6/8 guinea pigs.
Information on the chronic toxicity of tetryl to humans or animals by other routes of exposure was not available.
Information on the developmental and reproductive toxicity of tetryl to humans or animals by other routes of exposure was not available.
Human occupational exposure to tetryl produces various toxic effects. Because occupational exposure occurs in areas that have high atmospheric concentrations of tetryl-laden dust, it is likely that a combination of oral exposure from the swallowing of dust impacted on the pharynx or from mucocilliary transport, inhalation exposure, and dermal exposure result in the observed tetryl-related toxic effects. Therefore, it is often not possible to attribute all of these effects to specific routes of exposure.
Kidney: Following oral exposure to tetryl, rats, and rabbits developed renal lesions that were characterized by focal areas of hypertrophy and convoluted tubular necrosis (Fati and Daniele, 1965; Daniele, 1964; Parmeggiani et al., 1956; Wells, 1920).
1. Liver: After oral exposure to tetryl, rats developed circumscribed areas of focal necrosis and vascular congestion (Fati and Daniele, 1965). The decreased coagulability of rabbit blood as reported by Daniele (1964) may be related to decreased production of clotting factors by the liver. Parmeggiani (1983) has reported that prolonged exposure to tetryl can induce chronic hepatitis.
2. Spleen: After oral exposure to tetryl, rats developed splenic atrophy that was accompanied by hemosiderosis.
3. Gastrointestinal Tract: After exposure to tetryl, human workers developed nausea, vomiting, abdominal cramps, and diarrhea (Parmeggiani, 1983). However, these effects may be related to central nervous system effects.
4. Central Nervous System: After exposure to tetryl, human workers developed malaise, fatigue, insomnia, exaggerated reflexes mental excitation and headaches. These are indicators of possible tetryl toxicity to the central nervous system. Gastrointestinal symptoms such as nausea, vomiting and abdominal cramps may also be related to central nervous system toxicity.
Upper Respiratory Tract: After exposure to tetryl, human workers developed irritation of the nasal and pharyngeal mucous membranes. This was accompanied by epistaxis, bronchial spasms and a dry cough (Parmeggiani, 1983).
Information on other target organs in humans and animals following inhalation exposure to tetryl was not available.
Skin: Humans occupationally exposed to tetryl developed a dermatitis characterized by erythema of the neck, chest, back and forearms following exposure to tetryl. After erythema regression, affected areas may undergo moderate desquamation. Dermal irritation by tetryl may also result in an allergic dermatitis (Witkowski, 1944; Parmeggiani, 1983; Goh, 1984).
Information on the carcinogenicity of tetryl to humans after oral exposure was not available.
Griswold et al. (1968) studied the ability of tetryl to produce tumors in rats. Twenty female Sprague-Dawley rats received a total of 400 mg tetryl/rat by gavage in ten equal doses dissolved in sesame oil over a 30 day period (equivalent to 114.3 mg/kg/gavage based on an assumed body weight of 0.35 kg). The rats were observed for a total of 9 months, at which time they were sacrificed. Although the study was designed principally for the detection of mammary tumors, various other tissues, including intestinal tract, pituitary, liver, ovarian and adrenal, were likewise processed for microscopic evaluation. The tumor incidence of the tetryl-treated rats was compared to a vehicle control group composed of 140 rats and a positive control group of 40 rats that received a single 18 mg/kg dose of the known mammary carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). At the end of the study, 1/19 (5%) of the rats treated with tetryl had developed mammary hyperplasia and 1/19 (5%) developed adenoma of the stomach. Rats treated only with sesame oil had a 5/132 (4%) incidence of mammary lesions (a total 3 carcinomas, 1 fibroadenoma and 5 hyperplasias were observed) whereas all rats in the DMBA treatment group had developed mammary lesions (25/29 rats had carcinomas or sarcomas).
Under the conditions of the study conducted by Griswold et al. (1968), treatment of rats with tetryl for 9 months did not increase the incidence of tumors when compared to vehicle-treated rats. However, it should be noted that this study was of inadequate duration (less than life time), used only one dose level (40 mg/kg/gavage), and used insufficient numbers of tetryl-treated animals (20) to fully evaluate the tumorigenic properties of tetryl.
Information on the carcinogenicity of tetryl to humans or animals after inhalation exposure was not available.
Information on the carcinogenicity of tetryl to humans or animals from other routes of exposure was not available.
EPA Classification -- D; not classifiable as to human carcinogenicity.
Basis -- Adequate cancer bioassays or epidemiological studies were not available to assess the carcinogenicity of tetryl.
Tetryl is in weight-of-evidence Group D and therefore dose not receive a slope factor for oral exposure.
Tetryl is in weight-of-evidence Group D and therefore dose not receive a slope factor for inhalation exposure.
Cripps, L. 1917. The properties of tetryl (as affecting the human system). Brit. J. Dermat. 29: 3-7. (Cited in Hardy and Maloof, 1950)
Daniele, E. 1964. Hemocoagulative modifications in chronic experimental poisoning by tetryl. Folia. Med. 47(8): 767-776. (Cited in U.S. EPA, 1990.)
Fati, S. and E. Daniele. 1965. Histopathological changes in experimental chronic tetryl poisoning. Folia. Med. 48(4): 269-276. (Cited in U.S. EPA, 1990.)
Gell, P.G.H. 1944. Sensitization to tetryl. Br. J. Exp. Pathol. 25: 174-192. (Cited in U.S. EPA, 1990.)
Goh, C.L. 1984. Allergic contact dermatitis from tetryl and trinitrotoluene. Cont. Dermat. 10(2): 108.
Griswold, D.P., A.E. Casey, E.K. Weisburger and J.H. Weisburger. 1968. The carcinogenicity of multiple intragastric doses of aromatic and heterocyclic nitro or amino derivatives in young female Sprague-Dawley rats. Cancer Res. 28: 924-933.
Hardy, H.L. and C.C. Maloof. 1950. Evidence of systemic effect of tetryl. Arch. Indus. Hyg. Occup. Med. 1: 545-555.
ITII (The International Technical Information Institute), 1986. In: Toxic and Hazardous Industrial Chemicals Safety Manual for Handling and disposal with Toxicity and Hazard Data, the International Technical Information Institute, Tokyo, Japan, pp. 514-515.
Kaye, S.M. and H.L. Herman. 1980. In: Encyclopedia of Explosives and Related Items, PATR 2700, Vol. 9., U.S. Army Armament Research and Development Command, Large Caliber Weapons Systems Laboratory, Dover, NJ., pp T 148-t 164.
Parmeggiani, L., E. Bartalini, C. Sassi, and A. Parini. 1956. Occupational experimental tetryl pathology: Experimental research, clinical observations and prevention. Med. Lavoro. 47: 293. (Cited in U.S. EPA, 1990.)
Parmeggiani, L. 1983. In: Encyclopedia of Occupational Health and Safety, 3rd ed., Vol. 2. International Labour Office, Geneva, Switzerland, pp. 2165-2166.
Sax, N.I. and R.J. Lewis. 1989. In: Properties of Industrial Materials, 7th ed., Volume III, Van Nostrand Reinhold Co., New York, NY, p. 3235.
Sittig, M. 1985. Tetryl. In: Handbook of Toxic and Hazardous Chemicals, 2nd ed., Noyes Publications, Park Ridge, NJ, pp. 852-853.
U.S. EPA. 1990. Health and Environmental Effects Document for Trinitrophenylmethylnitramine. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-G091.
Wells, H.G., J.H. Lewis, W.D. Sansum, W.B. McClure and H.O. Lussky. 1920. Observations on the Toxicity of tetranitromethylaniline (tetryl), tetranitroxylene (T.N.X.), tetranitraniline (T.N.A.), dinitrodichlorobenzene (Parazol) and metamitaniline. J. Ind. Hyg. 2: 247-252.
Whitkowski, L.J., C.N. Fischer and D. Murdock. 1942. Industrial illness due to tetryl. J. Am. Med. Assoc. 119: 1406-1409. (Cited in U.S. EPA, 1990.)
Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein. 1983. In: The Merck Index, 10th ed. Merck and Co., Inc., Rahway, NJ., pp. 942-943.
Zambrano , A. and S. Mandovano. 1956. Urinary excretion of picric acid, picramic acid and of sulfoconjugation products in experimental tetryl poisoning. Folia. Medica. 39: 161-171. (Cited in U.S. EPA, 1990.)Retrieve Toxicity Profiles Condensed Version
Last Updated 2/13/98