DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
PUBLIC HEALTH SERVICE
CENTER FOR DISEASE CONTROL
NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH
5600 FISHERS LANE
ROCKVILLE, MARYLAND 20852
October 24, 1975
Dear Colleague:
The enclosed background material on Hexamethylphosphoric
Triamide has been prepared by the Office of Occupational Health
Surveillance and Biometrics, National Institute for Occupational
Safety and Health to alert members of the occupational health
community to new infomation on a potential occupational hazard.
Your comments and suggestions for changes to future reports
are solicited.
Sincerely yours,
[signature]
J. William Lloyd, Sc.D., Director
Office of Occupational Health
Surveillance and Biometrics
The National Institute for Occupational Safety and Health (NIOSH) has
received a report from an American producer of hexamethylphosphoric triamide (HMPA), a synthetic organic chemical, indicating that malignant tumors have been produced in laboratory animals by exposure to HMPA.
In light of the potential risk of human exposure to this chemical in
the work environment, the National Institute for Occupational Safety and Health is advising the occupational health community of these findings.
The E.I. du Pont de Nemours and Company (Du Pont) reported to the
National Institute for Occupational Safety and Health in a letter dated
September 24, 1975, that nasal tumors (squamous cell carcinoma) have been
observed in rats exposed to hexamethylphosphoric triamide. NIOSH has also
been advised that Du Pont has notified its customers and employees of
these findings.
HMPA is a colorless liquid with a density of 1.03 g/ml and a boiling
point of 232°C. Synonyms for hexamethylphosphoric triamide include ENT
50882, hempa, hexametapol, hexamethylphosphamide, hexamethylphosphoramide,
hexamethylphosphoric acid triamide, hexamethylphosphorotriamide, hexamethylphosphotriamide, HMPA, HMPT, HPT, phosphoric tris (dimethyamide),
phosphoryl hexamethyltriamide, tris (dimethylamino) phosphine oxide, and
tris (dimethylamino) phosphorous oxide.
1
Hexamethylphosphoric triamide is a material possessing unique solvent
properties and is widely used as a solvent, in small quantities, in organic
and organo-metallic reactions in laboratories.
2,3 This is the major
source of occupational exposure to HMPA in the United States.
Du Pont, the major manufacturer of hexamethylphosphoric triamide in
the United States, periodically produces HMPA at its Chambers Works, Deepwater, New Jersey. Other producers of HMPA in the United States include
Chemical Samples Company and Fike Chemical Company. None of Du Pont's
HMPA is marketed; all is used internally at its Spruance Plant in Richmond,
Virginia, as a processing solvent in the production of
Kevlar* aramid fiber. Du Pont reports that Kevlar contains less than 1 ppm (w/w) of the HMPA which is so firmly held by the fiber that Du Pont believes there is no hazard to customers or employees handling the final fiber product.
Hexamethylphosphoric triamide had been manufactured and distributed
in the past by Dow Chemical Company ( as DORCOL) and Eastman Chemical
Products, Inc. ( as Inhibitor HPT). Both firms have advised NIOSH that
they discontinued these products several years ago.
4 HMPA has been evaluated for use as an ultraviolet light inhibitor in polyvinyl chloride formulations, as an additive for antistatic effects, as a flame retardant, and as a de-icing additive for jet fuels.4-6
Hexamethylphosphoric triamide has also been extensively investigated as an insect chemosterilant.7,8
HMPA is known to have a variety of toxic effects on laboratory
animals. Acute toxic effects seen in rats fed HMPA include kidney
disease, severe bronchiectasis and bronchopneumonia with squamous
metaplasia and fibrosis in lungs.9,10 In rabbits, repeated application of HMPA to the skin caused dose related weight loss, altered gastrointestinal function and apparent nervous-system dysfunction.
ll
Testicular atrophy and aspermia have been observed in rats following oral
treatment with HMPA.9,12 Oral treatment with HMPA has also been highly inhibitory to testicular development in cockerels.13
HMPA is known to produce mutagenic effects in fruit flies (Drosophila
melanogaster).14 However, studies of the effects of HMPA on human15 and mice chromosomes
16 showed no greater frequency of HMPA induced chromosomal aberrations when compared with controls.
Preliminary results of an inhalation toxicity study of HMPA, recently
released by Du Pont, show nasal tumors in rats exposed daily to 400 and
4,000 parts per billion (ppb) HMPA after 8 months of exposure. In some
cases, the tumors originating from the epithelial lining of the nasal
turbinate bones filled the nasal cavity and penetrated into the brain. No
nasal tumors were reported among rats exposed to 50 ppb HMPA and controls.
Prior to the Du Pont observations, the only other known report of
tumors associated with exposure to HMPA was a long-term feeding study
by Kimbrough. While lung tumors were observed, the results of this
study were inconclusive because the tumor incidence among HMPA exposed
rats was not greater than among the control rats.
17
It is estimated that 5,000 people are occupationally exposed to
hexamethylphosphoric triamide. More than 90 percent of these exposures
are in research laboratories.
CHEMLINE, National Library of Medicine, Bethesda, Maryland, October,
1975
Fieser, M. and Fieser, L.F.: for Organic Synthesis, John
Wiley and Sons, Inc., New York, 4:244, 1974; 3:149, 1972; 2:208, 1969;
1:430, 1967
Chemical Abstracts, Chemical Substances Index, Chemical Abstracts
Service, Columbus, Ohio, Vol. 81, 1974
Personal communication with representatives of Dow Chemical Company,
Midland, Michigan, and Eastman Chemical Products, Inc., Kingsport,
Tennessee
Eastman Technical Data Sheet No. X-203, Eastman Chemical Products,
Inc., Kingsport, Tennessee
The Merck Index, 8th Ed., Merck and Company, Inc., Rahway, New Jersey,
p. 528, 1968
Bull, D.L. and Borkovec, A.B.: of Carbon-14-Labeled Hempa by Adult Boll Weevils, Arch Environ Contam Toxicol, 1(2):148-58, 1973
Landa, V.: of Chemosterilants in the Reproductive Organs and Tissues of Insects, Proc, Int Cong Entomol, 13th, 3:423-24, 1972
Kimbrough, R.D. and Gaines, T.B.: of Hexamethylphosphoramide in Rats, Nature, 211:146-47, 1966
Kimbrough, R.D. and Sedlak, V.A.: Morphology in Rats Treated
with Hexamethylphosphoramide, Toxicol Appl Pharmacol, 12(l):60-7, 1968
Shott, L.D., Borkovec, A.B., and Knapp, W.A., Jr.: of
Hexamethylphosphoric Triamide in Rats and Rabbits, Toxicol Appl
Pharmacol, 18(13):499-506, 1971
Jackson, H., Jones, A. R., and Cooper, E.R.A.: of Hexamethylphosphoramide on Rat Spermatogenesis and Fertility, J Repro Fertil, 20:263-69, 1969
Sherman, M. and Herrick, R.B.: Toxicity of Five Insect Chemosterilants, Hemel, Hempa, Tepa, Metepa, and Methotrexate, for Cockerels, Toxicol Appl Pharmacol, 16:100-07, 1970
Benes, V. and Sram, R.J.: Activity of Some Pesticides in
Drosophila Melanogaster, Indus Med Surg, 38(12):442-44, 1969
Chang, T.H. and Klassen, W.: Effects of Tretamine, Tepa, Apholate, and Their Structural Analogs on Chromosomes in Vitro,
Chromasoma, 24(3):314-23, 1968
Manna, G.K. and Das, P.K.: of two Chemosterilants Apholate and Hempa on the Bone-Marrow Chromosomes of Mice, Can J Genet Cytol, 15(3):451-59, 1973
Kimbrough, R.D. and Gaines, T.B.: Chronic Toxicity of Hexamethylphosphoramide in rats, Bull Environ Contam and Toxicol, 10(4)225-26, 1973
Copies of this and other NIOSH documents are available from: