National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Trimethylphosphate
• PHOSPHORIC ACID, TRIMETHYL ESTER (9CI)

Human Toxicity Excerpts

• TOXIC BY INGESTION & INHALATION. [Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987., p. 1190]**PEER REVIEWED**
  
• Weakness and paralysis are neurotoxic effects of trimethyl phosphate. /From table/ [O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985., p. 138]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• MUTAGENICITY: MUTATION RESEARCH 87: 143 (1981). MAMMALIAN CYTOGENETICS - IN VIVO LEUCOCYTE OR LYMPHOCYTE STUDIES, HUMAN: POSITIVE. [GENE-TOX Program: Current Status of Bioassay in Genetic Toxicology. U.S. Environmental Protection Agency, Washington, DC. Office of Toxic Substances and Pesticides. (For program information, contact Environmental Mutagen Information Center, Oak Ridge National Laboratory, Post Office Box Y, Oak Ridge, Tennessee 37830. Telephone (615) 574-7871), p. ]**PEER REVIEWED**
  
• RABBIT ADMIN 0.3 ML/KG/DAY FOR 6 DAYS ORALLY & 2.0 ML/KG/DAY FOR 20 DOSES ON SKIN PRODUCED FLACCID & SPASTIC PARALYSIS. CAT ADMIN 0.1 ML/KG/DAY FOR 79 DAYS SC PRODUCED LOSS OF WEIGHT & WEAKNESS. /FROM TABLE/ [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 2370]**PEER REVIEWED**
  
• MICE ADMIN 250 OR 500 MG/KG TMP BY GAVAGE 3 TIMES/WK FOR 103 WK. NO SIGNIFICANT INCR OF TUMORS IN MALES. IN FEMALES INCIDENCE OF ADENOCARCINOMAS OF ENDOMETRIUM HIGHER IN HIGH-DOSE GROUP THAN IN CONTROLS. [DIV CANCER CAUSE PREV, NATL CANCER INST, BETHESDA; CARCINOG TECH REP SER-US NATL CANCER INST (NCI-CG-TR-81) 1978]**PEER REVIEWED**
  
• RATS ADMIN 50 OR 100 MG/KG TRIMETHYLPHOSPHATE 3 TIMES/WK BY GAVAGE FOR 104 WK. INCIDENCE OF FIBROMAS OF SC TISSUE HIGHER IN HIGH DOSE GROUP OF MALES THAN CONTROLS. NO SIGNIFICANT INCR OF TUMORS IN FEMALES. [DIV CANCER CAUSE PREV, NATL CANCER INST, BETHESDA; CARCINOG TECH REP SER-US NATL CANCER INST(NCI-CG-TR-81) 1978, 98 PP]**PEER REVIEWED**
  
• TRIMETHYLPHOSPHATE INDUCED STERILITY IN MICE, RATS & RABBITS. TRIMETHYLPHOSPHATE PRIMARILY AFFECTED EPIDIDYMAL SPERMATOZOA, PROBABLY BY ACTION OF SPERM MOTILITY. [HARBISON RD ET AL; TOXICOL APPL PHARMACOL 35: 481 (1976)]**PEER REVIEWED**
  
• TRIMETHYL PHOSPHATE WAS ADMIN TO MALE MICE BY IP INJECTION OF 200-2000 MG/KG OR ORALLY IN DAILY DOSES FOR 5 DAYS OF 500 OR 1000 MG/KG. THESE SUBTOXIC CONCENTRATIONS PRODUCED BOTH ANTIFERTILITY & MUTAGENIC EFFECTS. [EPSTEIN SS ET AL; SCIENCE; 168 (3931): 584 (1970)]**PEER REVIEWED**
  
• TRIMETHYLPHOSPHATE CAUSES ASPERMIA IN DROSOPHILA MELANOGASTER MALES. [HANNA PJ; AUST J BIOL SCI 33 (5): 563 (1980)]**PEER REVIEWED**
  
• The toxic effect of trimethyl phosphate on rat testes was investigated after oral dosing with 250 mg/kg for either 5 days per wk for 30 days or 6 days per wk for 60 days. After these prolonged treatments spermatozoa obtained from the epididymis of treated rats were all abnormal and complete loss of germ cell activity was observed. Treated males also demonstrated a lack of mating ability ... . Clearly, by extrapolating from acute and sub-acute studies described above, long term administration of trimethyl phosphate will have a lasting antifertility effect. [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 485]**PEER REVIEWED**
  
• In Japanese quail treated orally with 5 daily doses of trimethyl phosphate at 250 mg/kg, there was rapid decline in the percentage of fertile eggs during the 10 day period following the first dose. This was followed by a short, but marked sterile phase for 7 days, with return to fertility comparable to controls by 25 days ... . In another study it was reported that only 81% of eggs laid between 1 and 35 days after treatment of male quail with trimethyl phosphate were fertile, significantly less than in the control group ... . [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 483]**PEER REVIEWED**
  
• After oral administration of a lethal dose to rats, guinea pigs, or rabbits, trimethyl phosphate induced a gradually decreasing rate and amplitude of respiratory movements, sometimes after a brief period of stimulation, general weakness, mild irritability and fine tremors. These signs were followed by dyspnea, collapse, and death by respiratory failure. Repeated administration of sublethal doses to rabbits resulted in similar signs and symptoms, frequently with loss of body weight and flaccid paralysis of the extremities, which in some instances was superseded by a spastic state of the affected muscles ... . [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 483]**PEER REVIEWED**
  
• Five beagle dogs were treated daily with 1 ml of trimethyl phosphate for 1 to 4 months. Effects on the nervous system were evaluated by observing the dog's behavior, neurologic examinations, neurophysiologic tests, and neuropathologic examination. After 4 wk, neurotoxicity was noted in impairment of hopping, tactile placing, and atactic gait. Electrophysiologic tests indicated a prolonged latency of neuromuscular impulse transmission after wk 9, followed by a decrease in maximum conduction velocity of sensory fibers. Peripheral nerve fibers also had abnormalities at this time, including paranodal and internodal swelling, paranodal demyelination, and distal fragmentation. One dog which received twice the dose 5 days per wk developed a severe distally accentuated degeneration of long spinal tracts and peripheral nerve fibers ... . [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 484]**PEER REVIEWED**
  
• A single ip dose to male mice of 1000 or 1500 mg/kg in dominant lethal and heritable translocation studies resulted in marked dose-dependent increases in early fetal deaths. F1 male progeny were sterile or semi-sterile, resulting from heritable translocations (14.3% at the higher dose and 5.3% at the lower dose). Thus, trimethyl phosphate is capable of causing chromosomal damage in mouse spermatids ... . [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 482]**PEER REVIEWED**
  
• Trimethyl phosphate rated 2 /on a scale of 1 to 10, with 10 being the most severe/ on rabbit eyes. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 1062]**PEER REVIEWED**
  
• A series of experiments were conducted to investigate the dependence of male reproductive toxicity on germ cell stage in rats. Glutathione levels were determined in segments of the reproductive tract in sexually mature male Fischer 344 rats with or without treatment with chemicals thought to have reproductive effects. Sexually mature male and female rats were used in a serial mating study of dominant lethal mutations. Clastogenic damage in male germ cell stage dependent dominant lethal mutations results from exposure to ethyl methanesulfonate. The most damage was induced among spermatozoa in late spermatid and early spermatozoal development. Germ cell stage dependent activity of ethyl methanesulfonate was potentiated by both L-buthionine sulfoximine and 1,2-dibromoethane. Both L-buthionine sulfoximine and 1,2-dibromoethane significantly reduced the epididymal glutathione content, likely the reason for the potentiation effect. At 8 and 16 hours post injection L-buthionine-sulfoximine treatment significantly depressed glutathione in the epididymis and testes. 1,2-Dibromoethane treatment significantly depressed glutathione at 2 hours in caput and cauda epididymis but not in the testes. Trimethyl phosphate was also able to produce clastogenic damage as well as functionally impair spermatozoa in a dose dependent manner. This impairment was also dependent on germ cell stage. Mature spermatozoa were about four times more susceptible to the actions of trimethyl phosphate, resulting in altered motility. Triethyl phosphate treatment caused a 20 percent reduction in cauda epididymal spermatozoa carnitine acetyltransferase activity. The authors conclude that overt chemical induced male reproductive toxicity may be dependent on germ cell stage but potency is markedly altered by biochemical influences. [Gandy J et al; Functional Teratogenesis 133-45 (1987)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Rat oral 840 mg/kg [Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984., p. 2674]**PEER REVIEWED**
  
• LD50 Rabbit oral 1050 mg/kg [Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984., p. 2674]**PEER REVIEWED**
  
• LD50 Mouse oral 1470 mg/kg [Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984., p. 2674]**PEER REVIEWED**
  
• LD50 Rabbit oral 1275 mg/kg [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 482]**PEER REVIEWED**
  
• LD50 Guinea pig oral 1700 mg/kg [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 482]**PEER REVIEWED**
  
• LD50 Mouse iv 2250 mg/kg [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 482]**PEER REVIEWED**
  
• LD50 Rabbit dermal 3400 mg/kg [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 482]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• Most organophosphate compounds are ... absorbed from skin, conjunctiva, gastrointestinal tract, & lung. /Organophosphate compounds/ [Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 1071]**PEER REVIEWED**
  

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Metabolism/Metabolites

• Rats treated orally at 100 mg/kg and mice treated ip at 1000 mg/kg with (32)P-labeled trimethyl phosphate excreted primarily dimethyl phosphate in the urine. Only traces of the parent compound were detected, and only in the rats at less than 6 hr after treatment. S-Methyl cysteine and S-methyl cysteine N-acetate were also isolated. Small amounts of S-methyl glutathione were detected, presumably the initial methylation product in this series of metabolites ... . Metabolism of trimethyl phosphate was faster in the mouse than in the rat, but there was no evidence of further conversion to monomethyl phosphate in either species ... . [Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990., p. 482]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.