PB-244 337
GUIDES FOR SHORT-TERM EXPOSURES OF THE PUBLIC TO AIR
POLLUTANTS. V. GUIDE FOR HYDRAZIfiE, MONOMETHYL-
HYDRAZINE, AND 1, 1-DIME-THYLHYDRAZINE
National Research Council
Prepared for:
Environmental Protection Agency
June 1974
DISTRIBUTED BY:
National Technical Information Service
U. S. DEPARTMENT OF COMMERCE
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NAS/ACT/P-628.6
Guides for Short-Term Exposures of the Public to Air Pollutants
V. Guide for Hydrazine,
Monomethylhydrazine, and I. 1-Dimethylhydrazine
by
The Committee on Toxicology
of the
National Academy of Sciences .- National Research Council
Washington, D. C.
June 1974
-------
DEMOGRAPHIC DATA
SHEET
1. Kcpoit No.
NAS/ACT/P-628,.6
PB 244 337
4. Title and Subtitle
Guides for Short-Term Exposures of the Public to Air
Pollutants. V. Guide for Hydrazihe, Monoethylhydrazine,
and 1,1-Dimehtylhydrazine.
5. Kcpoit Date
June 1974
6.
7. Author(s)
i. Performing Organization Kc(K.
No- NAS/ACT/P-628.6
9. Performing Organization Name and Address
Committee on Toxicology of the National Academy of Sciences
National Research Council
2101 Constitution Avenue, N.W.
Washington. DC 20418 •
10. Project/Task/Wotk Unit No.
II. Contract/Cram No.
CPA 70-57
68-01-C132
12. Sponsoring Organization Name and Address
Environmental Protection Agency
4th and M Streets, S.W.
Washington, DC 20460
IX Type of Report & Period
Covered
Final
14.
IS. Supplementary Notes
16. Abstracts
Recommendations are made for limits of air concentrations of hydrazine,
monoethylhydrazine, or 1,1-Dimethylhydrazine to which the public may
safely be exposed for short periods of time. The scientific basis and
associated literature references for the recommendations are presented.
17. Key Words and Document Analysis. 17o. Descriptors
Air pollution
Hydrazines
Exposure
Sensitivity
Toxicity
• • ' • '
I7b. Identificrs/Opcn-Ended Terms
Air pollution effects (animals)
Air pollution effects (animals)
Short-Terra Public Limits (STPL's)
Public Emergency Limits (PEL's)
i
17c. COSATI Field/Group 13B '
Hydrazine
Monoethylhydrazine
1,1-Dimethylhydrazine
18. Availability Statement
Release unlimited.
I.
19.. Security Class (This
Report)
UNCLASSIFIED
20. Security Class (This
Page
UNCLASSIFIED
21. No. of Pages
60
22. Price
FORM NTIS-3S 110-70)
USCOMM^DC 40329-P71
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Committee on Toxicology
. Bertram D. Dinman, Chairman Charles F. Reinhardt
Arthur B. DuBois, Vice Chairman C.'Boyd Shaffer
Yves Alarie . Frank G. Standaert
Seymour L. Friess Richard D. Stewart
Harold M. Peck Herbert E. Stokinger
Subcommittee on Hydrazine,
Monomethylhydrazine, and 1, 1-Dimethylhydrazine
C. Boyd Shaffer, Chairman, American Cyanamid Company
Kenneth C. Back, Wright-Patterson Air Force Base
Frank N. Dost, Oregon State University
Richard Henderson, Olin Corporation
James D. MacEwen, University of California (Irvine)
Keith H. Jacobson, Reviewer, National Institute for
Occupation Safety and Health
Dale A. Clark, Reviewer, School of Aerospace
Medicine
Joan H. Broome (Staff Officer)
Frank G. Favorite (Staff Officer)
Joan C. Standaert (Consultant)
Ralph C. Wands (Staff Officer)
Ralph C. Wands, Director
Advisory Center on Toxicology
National Academy of Sciences-National Research Council
IA/
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NOTICE
The project which is the subject of this report was
approved by the Governing Board of the National Research
Council, acting in behalf of the National Academy of Sci-
ences. Such approval reflects the Board's judgment that
the project is of national importance and appropriate with
respect to both the purposes and resources of the National
Research Council.
The members of the committee selected to undertake
this project and prepare this report were chosen for recog-
nized scholarly competence a.»d with due consideration for
the balance of disciplines appropriate to the project.
Responsibility for the detailed aspects of this report rests
with that committee.
Each report issuing from a study committee of the
National Research Council is reviewed by an independent
group of qualified individuals according to procedures
established and monitored by the Report Review Committee
of the National Academy of Sciences. Distribution of the
report is approved, by the President of the Academy, upon
satisfactory completion of the review process.
it.
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Prepared under Contract No. CPA 7057 and
Contract No. 6B-01-0132 between the National
Academy of Sciences. Advisory Center on Toxi-
cology and the Office of Air Programs of the
Environmental Protection Agency.
Contract' Monitor:
Dr. John Wesley Clciyton, Jr.
Chief, Toxicology Branch
Health Effects Division
. Environmental Protection Agency
Washington. D. C. 20460
The Panel and the Committee express their
sincere appreciation to Mrs. Standaert for
her services as a consultant in the final
preparation of this Guide.
1C,
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CONTENTS
I. .Introduction
II. Guide for Hydrazine
III. Guide for Monomethylhydrazine
IV. Guide for 1, 1-Dimethylhydrazine
V. Analytical Methods
VI. References
VII. APPENDIX: Tables
(I) . Physical Properties
(2) Acute Toxicity (L,D5())
(3) Inhalation Toxicity (LCg )
(4) Recommended Limits for Exposure
id
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I. INTRODUCTION
•
The search for improved rocket fuels to expedite exploration of
space led to the introduction of hydrazine, monomethylhydrazine (MMH)
and unsymmetrical dimethylhydrazine (UDMH) as fuels in propellant
systems. These compounds are all storable; non-cryogenic, high-
energy fuels that may be used alone or in combination as mixed amine
fuels. In addition, hydrazine and its derivatives are finding increasing
commercial application as intermediates in the synthesis of other
products. Because of these developments substantial amounts of
hydrazine. MMH and UDMH are presently manufactured, stored, and
shipped in the United States. These materials are all toxic and would
present a hazard to the public if they should be accidentally released
into the environment.
The Committee on Toxicology of the National Academy of Sciences -
National Research Council (1971) has previously recommended Emer-
gency Exposure Limits (EELi's) for exposures to the vapors of hydra-
zine, MMH and UDMH. These limits are applicable only to personnel
directly involved in spacecraft operations. At the request of the
Environmental Protection Agency the Committee has prepared this
document, which includes recommended limits for short-term ex-
posures of the public to these pollutants. The Committee and Panel
members have been confronted with several difficulties in arriving at
these recommendations. Data on the toxicity of the hydrazines from
animal studies are not as complete or consistent as desired; their
extrapolation to the human situation is complicated by the fact that
there are marked differences in species response to these agents.
Furthermore, it has not been possible to survey these compounds as a
homogeneous group because their differing physical characteristics
and physiologic actions give rise to wide variations in potential toxic
effects.
Most accidental exposures to these liquids would probably occur
from spills that may result in toxic effects from.inhalation and/or
extensivje direct skin contact. UDMH has the highest vapor pressure
of the three compounds and presents the greatest inhalation hazard.
All three are absorbed through the skin but since UDMH vaporizes
most readily it represents the lowest hazard from cutaneous exposures.
Exposures to mixed amine fuels may also occur. Aerozine "50", a
widely used mixed amine fuel, is a 1:1 mixture by weight of hydrazine
and UDMH. In halation hazards from spills of this liquid arise mainly
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from UDMH^v/hile systemic toxic effects from skin contact are those of
hydrazine.
All these compounds are convulsants as well as irritants to the eyes,
skin, and respiratory tract. The magnitude of these effects varies
widely among the three, and two have unique toxic actions. Hydrazine
can cause delayed death from liver damage following acute or repeated
exposures. MMH can cause hemolytic effects in man and animals.
Experimental1, studies have also shown that the convulsant action of
UDMH and MMH may be alleviated by the use of pyridoxine but this
agent does not protect against the convulsant effects of hydr^zine.
.At the present time there is not enough information to speculate on
the mechanisms of the toxicities that have been described. . It is evi-
dent that a great deal of additional information is needed before we can
truly assess the hazards these compounds present to human health.
The toxicology of these compounds is discussed ir. separate chapters,
with recommended exposure limits. These limits are summarized in
Table 4. A separate chapter is devoted to analysis and monitoring.
There is a body of evidence from animal experiments that hydra-
zin; and many of its derivatives, including MMK and UDMH, over a
prolonged period of repeated or continuous exposure may increase the
number of tumors appearing near the end of the life span of the animals.
It is believed that the short-term exposures of the public as contempla -
ted in this Gaide do not constitute a tumorigenic risk under the condi-
tions and limits described here.
The Committee and its ad hoc Panel urge that a careful examiifcttion
be undertaken of the tumorigenic risk, to those who are occupationa-tty
exposed to hydrazine and its derivatives. It is further recommended
that a close surveillance of the literature be maintained for new data
that might require the modification of the foregoing comments and a
re-evaluation of the uses of these materials. Additional research on
the potential carcinogenicity of these compounds should be conducted.
-11-
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II. GUIDE FOR HYDRAZINE
Background
Hydrazine (H^NNH ) is an extremely reactive compound that
ordinarily does not occur free in nature. Because of its many unusual
properties, chemists have long been interested in isolating and
characterizing hydrazine and its salts and derivatives. These experi-
ments have produced a large literature dating back to 1875.
The status of hydrazine as an exotic chemical changed during World
War II when Germany began using hydrazine as a rocket fuel and
developed a process that produced the compound on a tonnage basis.
These events stimulated commercial interest in hydrazine and sub-
sequently the first plant for the production of anhydrous hydrazine in
the United States commenced operation in 1953.
Commercial Uses of Hydrazine
At the present time somewhere between ten and twenty million
pounds of hydrazine are produced annually in tr.o United States. The
largest proportion of current production, about seven million pounds
annually, is used for the preparation of derivatives that are applied
in the formulation of plastics, rubber products, photographic supplies,
insecticides, dyes, textiles, pharmaceuticals, and other products.
About 100,000 pounds a year of hydrazine salts, mainly the hydrochlo-
ride or hydrobromide, are prepared and shipped for use as a soldering
flux. In addition, about 1, 000, 000 pounds annually are shipped in
aqueous solution (35-44%) for use as an oxygen scavenger in boiler
water. This amount will probably increase. Varying amounts of
anhydrous hydrazine are shipped for use as a rocket fuel. In 1963-64
about 11, 000, 000 pounds of anhydrous hydrazine wt re used for this
purpose, but current consumption is less than 1,000,000 pounds a year.
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The Physical and Chemical Properties of Hydrazine
Anhydrous hydrazine is a colorless, oily, hygroscopic liquid at
room temperature, fuming in air, with a penetrating odor resemh'mg
that of ammonia. Hydrazine can be distilled at temperatures about
113. 5°C. It is an extremely irritating gas, exhibiting a great affinity
for water and a marked tendency to conde '.so or to be adsorbed onto
surfaces including metallic interfaces, chamber walls, and the fur
of animals. It is quite difficult to prepare anhydrous hydrazine from
aqueous solution because of its great affinity for water. However, it
has been shown that solutions containing 85% or more hydrazine be-
have essentially like anhydrous hydrazine.
Hydrazine is notable for its great reactivity with a wide variety of
reagents including the halogens, alkali metals, and sulfur dioxide. It
is a powerful reducing agent and servee as a solvent for many inorganic
substances. It is miscible with water and lower aliphatic alcohols.
In aqueous solution hydrazine is a slightly weaker base (pKa. of 8. 07)
than ammonia. The concentration of such solutions is conventionally
specified as mole % hydrazine hydrate {N,H.. H2O; M. W. = 50.).
Hydrazine and water form an azeotropic mixture at 55 mole %
(bp_/Q = 120. 3°C). tt should also be noted that aqueous solutions of
hydrazine reduce molecular oxygen quite rapidly; therefore, dilute
solutions of hydrazine will deteriorate appreciably on contact with the
atmosphere. Autoxidation is a complex reaction that is affected by
PH (Audrieth and Ogg, 1951; Moeller,' 1952).
Hydrazine burns in air with the liberation of 148. 6 kilocalories per
mole. It. may ignite, spontaneously on contact with oxidants like hydrogen
peroxide and nitric acid or porous materials such as earth, asbestos,
wood, or cloth. Hydrazine is considered reasonably thermostable and
Thienes jet_al; (1948) have shown that it is not particularly susceptible
to detonation by impact. However, it v/ill decompose explosively on
sparking at 100°C or at temperatures above 350°C. Some of the per-
tinent physical constants of hydrazine are listed in Table 1. For more
information the reader is referred to the comprehensive review by
Audrieth and Ogg (1951)
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Effects On Animals
Acute Toxicity
After exposure to hydrazine, animals may d»e within a few hours
on convulsions, respiratory arrest. or cardiovascular collapse; or two
to four days later of kidney or liver injury (Weir Łt^al^ 1964; Witkin,
1956). When this delayed death is taken into account, the single-dose
L.D,.- of hydrazine is not marKedly different regardless of the route of
administration (Krop. 1954; Witkin, 1956). The acute toxicity of hydra-
zine by oral and parenteral routes is given in Table 2.
The 4-hour L>CCQ of hydrazine vapor is 254 ppm for mice and 580
ppm for rats according to Jacobson et_al^ (1955). Comstock et al.
(1954) reported a one-hour L«C_f. of 640 ppm for rats, although this
value is a "nominal" concentration and is probably higher than the
actual concentration.
It is interesting to note that the lethal dose of hydrazine vapor
calculated from L.CJ.Q (lethal concentration at constant time) o.r LT5Q
(lethal time at constant concentration) data does not differ appreciably
from the LiDcn obtained from oral or parenteral administration to
rodents. Such "maximum inhaled doses" assume complete retention
of inhaled material (Clark et al. 1968) and are calculated as the pro-
duct of the concentration of hydrazine in the vapor, duration of ex-
posure, and minute volume (average volume of air reaching the
alveoli per minute) of the species divided by body weight. However,
agreement with l^Drn values is good onl-t within a moderate range of
vapor concentrations. The correlation fails at concentrations that
are sufficiently irritating to cause a decrease in tHal volume (average
volume of inspired air in a single breath) by shallow breathing, or
which decrease the rate of respiration and minimize physical activity.
Repeated Dose Toxicity .
The lethality of hydrazine is approximately the same whether it
is given in a large single dose or in art equivalent amount supplied in
small discontinuous doses, e. g. , daily. Furthermore, the accumu-
lated lethal dose appears to be similar for all routes of absorption,
including inhalation.
Patrick and Back (1964) gave daily intraperitoneal injections of
hydrazine to monkeys and rats for various periods of time on a 5
days/week schedule. Four monkeys received 20 doses of 5 mg/kg, 6
received 4-5 doses of 20 mg/kg, and 2 received 20 doses of 5 mg/kg
followed by 8 doses of 10 mg/kg and 4-5 doses of 20 mg/kg. None of
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the animals died, although weakness, lethargy, emesis and weight loss
were noted. Twenty-five rats were given 10 mg/kg./day for 5 weeks,
and an equal number received 20 mg/kg/day for the same period of
time. All animals survived the lower dose, hut at the higher dose 10/25
died between the eighth and twenty-first doses. When Comstock et at.
(1954) exposed rats 6 hr/day, 5 days/week, to hydrazine vapor, 54 ppm
killed 14/16 in 4 to 13 exposures; 20 ppm killed 11/13 in 13 to 30 expo-
sures; 14 ppm killed 23/30 in 1 to 105 exposures; and 5 ppm killed 2/10
with deaths in the twenty-eighth week. Similar daily exposures of dogs
at 5 ppm over a 6-month exposure produced no deaths and very little
pathology. However, elevating the concentration to 14 ppm produced
marked effects and some deaths.
House (1964) found a high mortality among monkeys, rats and
mice exposed to a concentration of 1 ppm of hydrazine vapor contin-
uously for 90 days. Although 8 of 10 monkeys lived, only 2 of 50 rats
and 2 of 100 mice survived. Most of the mice died within 4 weeks,
while about half of the rats died between the sixth and tenth weeks.
Kulagina (1962) has found that a single 2-hour exposure to very
small concentrations of hydrazine vapor (19 ppm; 0. 6 mole/liter)
caused detectable changes in the conditioned reflex responses of rats
and mice. Th»re were no deaths among rats exposed to 0. 74 - 4 ppm
(0.03 - 0.16 mmole/1) hydrazine vapor 4 hr/day, 6 days/week, for 7
moaths, but these animal's showed effects on kinds of behavior that
require coordinated function of the nervous system. These functions
returned to normal 3-4 weeks after the exposure.
Weatherby and Yard (1955) have reported on exposures to small
amounts of hydrazine vapor over an extended period of time. Guinea
pigs exposed to 5-6 mg/m^ (4-5 ppm) for 6 hr/day, 5 days a week for
47 days had no deaths, although at autopsy their lungs showed pneumon-
itis and diffuse atelectasis. Clark Łt_al,._ (1968) have calculated the
"maximum inhaled dose" for these exposures as 34-68 mg/kg/day.
These same authors also gave young rats hydrazine in water at concen-
trations of 0.10. 0.20, 0.50, 1.00, and 2. 00 mg/ml. Daily doses''at
these concentrations amounted to about 16, 26, 96, 128, and 192 mg/kg/
day, respectively. The animals were reluctant to accept concentrations
over 0. 5 mg/ml a:,d several animals receiving this amount or more
died. Doses of 16 - 26 mg/kg/day did not produce any deaths or
pathology after be.ng ingested for 14 weeks. The stability of hydrazine
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in water is a'direct function of the dissolved oxygen, which raises some
question regarding the significance of hydrazine administered in
drinking water.
Tissue Pathology
In 1908 Underbill and Kleiner found that the liver is the chief site
of structural damage after hydrazine intoxication of dogs (100 mg/kg
B.C.). Wells (1908), reporting on the results of his histologic examina-
tions of these dogs, emphasized the remarkably specific destruction of
the cytoplasm of the parenchymatous cells of the liver, which began at
the center of the lobule. The cell nuclei appeared intact but were sur-
rounded by an overwhelming infiltration of fat. No'other tissue appeared
to be -imaged. Amenta and Johnston (1962) reaffirmed th?se ob-
servations in rodents. Subcutaneous administration of 2 x 10~^ moles
/kg hydrazine caused periportal and midzonal accumulation of liver
fat and loss of liver glycogen, with recovery of all observed function
within 3 to 4 days post-administration.
Single exposures of rodents to lethal (2,000 ppm) or sublethal
(800 ppm) concentrations of hydrazine vapor for 1-2 hours did not
produce liver damage (Thienes eŁ.aL , 1948), but concentrations that
caused death after one or more days did produce accumulation of fat
in the liver. There v/ere some deaths among rats and mice exposed to
.6 mg/m or 18 mg/m^ hydrazine vapor for 6 hr/day for 30 weeks.
(Comstock jet_al^, 1954), but there was ho evidence of liver pathology.
Some pulmonary congestion, emphysema, and atelectasis were noted.
In similar experiments rats were exposed to 6 mg/m hydrazine vapor
for 5 days a week for 18 weeks, Weatherby and Yard (1955) noted
central-zone fatty changes in the liver and kidney congestion and areas
of emphysema in the lungs. However, they found no pathology in
animals that ingested 15-25 mg hydrazine daily in drinking water.
From the above it is apparent that hydrazine produces pathology
in the lungs as well as the liver. While it is possible that these pul-
monary effects are due to local irritation caused by inhalation.
Thienes Łi.al_. (1948) have concluded that hydrazine has a direct effect
on pulmonary tissue since they observed that toxic doses of hydrazine
given by any route of administration affected the endothelium of blood
vessels, particularly those in the lung.
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Most of-the pathology of hydrazine intoxication has been studied in
rodents. However, Patrick and Back (1964) showed that fatty change
in the liver takes place at much lower dosages in monkeys than in
rats. Monkeys receiving 20 mg/kg daily for 7 days exhibited marked
lipid accumulation in the liver, the kidneys, myocardium, and skeletal
muscle. Massive liver necrosis w?.s observed in one of the six
animals.
Absorption, Distribution, and Excretion^
Hydrazine is absorbed by many routes (Table 2). Recently, Smith
and Clark (1972) have reported on the absorption of hydrazine through
the intact skin of anaesthetized dogs. Topical application of high doses
(3-15 mmoles/kg) (96-480 mg/kg) of hydrazine produced detectable
amounts of hydrazine in plasma within thirty seconds. The kinetics of
this process are not clear since dogs receiving the same dose of
hydrazine attained different plasma concentrations of the compound and
furthermore did not show any correlation between plasma and urinary
concentrations of hydrazine. However, the authors believe that the
rapidity of hydrazine absorption may be dose-related since the increase
of the sixty-minute plasma concentration over the ten-minute value is
a function of the amount of hydrazine applied.
Although the metabolic fate of hy'drazine is unknown, it has been
shown that some hydrazine is eliminated unchanged in the urine.
McKennis_eŁ ah (1955) reported that 5-il% of an intravenous dose
(50 mg/kg) of hydrazine sulfate was excreted by anaesthetized dogs
after four hours. Within two days 50% of the dose of hydrazine sulfate
was excreted by unanaesthetized dogs that received 15 mg/kg by intra-
venous injection. Evidence for a two-step in vivo acetylation of
hydrazine following intraperitoneal injection of rabbits was reported by
McKennis e^al^ (1959). This appears to be a detoxification mechanism.
Dambrauskas and Cornish (1964) found that rats given 60 mg/kg of
hydrazine s. c. excreted 8% and 27% after two and twenty hours, res-
pectively.
Effects on Metabolism and Enzymes
Hydrazine produces a variety of metabolic effects, yet the bulk of
investigative work has focused on the liver and the central nervous
system. Hydrazine may cause a transient hyperglycemia followed by
hypoglycemia. This sequence occurs during the first four hours fol-
lowing intravenous* injection to dogs and has been associated with
6
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depletion of glycogen stores in both liver and muscle (Taylor, 1966).
Hydrazine has been found to inhibit the formation of carbohydrate from
amino acid precursors (Lewis and Izume, 1926; Amenta and Johnston,
1963). Ray et_aL_ (1970) have found that one site of inhibition is the
conversion of oxaloacetate to phosphoenolpyruvate. Hydrazine also
interferes with glycogen formation in the liver following glucose
administration (Izume and Lewis, 1926; Amenta and Dorhinguez, 1965).
The hypoglycemia in hydrazine-treated, farted rats is associated with
elevations in the concentration of free fat:y acids in the plasma, the
total fatty-acid content of the liver, ana .he hepatic secretion of trigly-
cerides into the blood (Trout, 1966). If blood glucose is kept high by
using rionfasted or carbohydrate fed rats, free fatty-acid levels in the-
plasma are not increased. Most of the work reporting accumulation cf
lipid in the liver and kidney following single or multiple doses of hydra-
zine has been done in the rat (Amenta and Johnston, 196E; Weatherby
and Yard, 1955; Dominguez_ejt aL , 1962; Patrick and Back, 1965). It
is not known how this deposition occu: s but Clark_eŁaL (1968) have
speculated that lipid peroxidation may play an important role in the
process. Some oxidative effects may be involved since Beyer (1943)
has shown that vitamin C protects against the hepatic damage.
Hydrazine interference with carbohydrate, fat, and amino acid
metabolism may be related to the fact that it produces a significant
decline in serum concentration of insulin as well as glucose in 18-hour
fasted rats (Potter et_aL_, 1969). Hydrazine can also impede the secre-
tion of insulin in response to-an administered glucose load (Aleyassine
and Lee, 1971K Aleyassine and Lee also have demonstrated that
hydrazine inhibits the production of insulin from pancreatic tissue in
vitro. They feel that this inhibition may result from the accumulation
of certain biogenic amines in the beta cells of the pancreas following
mono-amine oxidase inhibition.
Other authors have suggested that some interference with amine
metabolism may also be responsible for the convulsant activity of
hydrazine in the central nervous system. However, at the present
time there are few reports of the effects of hydrazine on amine
metabolism in intact animals. Reed et_ah (1964) showed that hydra- .,
zine strongly inhibits the oxidation of putrescine and methylamine to
CO^ by intact rats. Hydrazine, unlike some of its derivatives, was
not found to be a mono-amine oxidase inhibitor, In vivo, but it did
appear to possess strong diamine oxidase suppressive activity. The
-------
compound partially inhibited the metabolism of large doses of L-alanine-
"C to l^cOj* and almost completely obstructed the conversion of gamma
aminobutyric acid (GABA) -l-14C to 14CO2. Medina (1963) showed that
rats injected with hydrazin.. iiad an inhibition of brain glutamic acid
dccarboxylase and GABA-transaminase and a concomitant rise in GABA.
However, he could not establish a direct relationship between the
convulsive action of hydrazine and the metabolism of GABA in whole
rat brain.
Other investigators have attempted to relate hydrazine toxicity to
the cofactors of GABA transaminase, (vitamin B, and its congeners).
Unfortunately, neither pyridoxine nor pyridoxul phosphate protects
against hydrazine convulsion in rats (Uchida and O'Brien, 1964) although
vitamin B(, does decrease the severity of convulsions initiated by some
hydrazine derivatives. Although Roberts and co-workers have found
that various mixtures of L-arginine, L-glutamatc, L-alanine, alpha-
ketoglutarate, and oxalacetate protect against hydrazine convulsions
in the mouse, there is little evidence that liver changes or other meta-
bolic effects are reduced (Roberts jet aJL . 1963, 1964, 1965).
These metabolic effects, some of which are produced by very low
doses, are transient and readily reversible. There is no evidence
that they are related to any of the overt manifestations of hydrazine
toxicity.
Cardiovascular Effects
The importance of cardiovascular toxicity from hydrazine remains
speculative. Walton _e_t al_. (1954) could not produce a significant effect
on heart contractile force in dogs at one-tenth to one-fourth the intra-
venous LDco (LDcQ = 25 mg/kg). They observed transient decreases in
blood pressure and ectopic rhythms at two to eight times the LD ..,
but death wa.s produced by respiratory rather than cardiac arrest.
Murtha and Wills (1953) demonstrated a gradual decrease in contractil-
ity of cat heart papillary muscle four to five hours after the addition
of hydrazine to the muscle bath. They postulated that toxic cardio-
vascular manifestations would probably not be observed until some time
after exposure.
Hayden and Murray (1965) studied the cardiopulmonary effects of
subacute hydrazine toxicity by right and left heart catherization, ex-
pired-gas analysis, and necropsy. Seven rhesus monkeys were given
-------
between 50 and 70 mg/kg i.p. over a three-day period. The animals
were ill, but not moribund. The monkeys lost weight, and arterial
blood pressure, cardiac and stroke index, systolic-ejection period,
tension-time index, left-ventricular-work index, oxygen-consumption
index, and arterial oxygen capacity decreased. Fatty myocardial
alterations present in six of the seven monkeys were attributed to de-
hydration and secondary metabolic disturbances, but a direct action
of hydrazine on the heart could not be excluded. Over all, doses re-
quired to produce marked changes in the cardiovascular system are
far in excess of those that can be attained reasonably by inhalation.
Tumor i genes is
There have been reports that hydrazine is a tumorigenic agent
and may possibly have some carcinogenic action in mice. Bianciftore
and Ribacci (1962) and Biancifiore_et: &L (1964) gave 1.13 mg of hydra-
zine eulfate, by mouth, to mice twice daily for 46 weeks. All develo-
ped multiple pulmonary tumors. Juhasz Łt_ah. (1966) injected mice
with 25 mg of hydrazine on sixteen occasions over a period of 46 days.
At this time 34 of 60 mice survived and subsequently 13 of the sur-
vivors developed myeloid leukemia or tumors (reticulum-cell sarco-
mata) within 100 to 313 days. However, Toth (1972) observed no sig-
nificant carcinogenesis when a 0. 012% solution of hydrazine sulfate
was the only drinking water ingested by randomly bred Syrian golden
hamsters during their lifetime. . .
Mutagenesis
Hydrazine may react in vitro under rather severe conditions
with the pyrimidine bases in nucleotides to form dihydro- or 4-hydra-
zino derivatives or to effect scission of the pyrimidine ring (Lingens
and Schneider-Bernloehr, 1965). The occurrence of similar reactions
in vivo could alter the base sequence in DNA or RNA and produce a
mutagenic effect. Some mutagenic effects of hydrazine have been
observed in bacteria but there have been no similar observations in
animals (Lingens, i96l).
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Effects On Plants
Hydrazine is poisonous to some plant seedlings. Heck_eŁal_. (1963)
found that 1, 000 ppm hydrazine in water decreased the number of
peanut and corn seeds that would germinate. Hydrazine concentrations
below 200 ppm reduced the germination of rice and peas but did not
affect the germination of alfalfa or endive. The growth of all four
was inhibited (Hoover ^al^, 1964).
Pinto bean plants and cotton seedlings grown in water containing
hydrazine showed inhibition of growth and dehydration of foliage.
Water solutions containing 300 ppm caused the death of cotton seed-
lings in 48 hours and 600 to 1,000 pprn caused death in 30 hours (Heck
et^al^, 1963).
Spraying of seedlings (cotton, pinto bean, soybean, endive, and
squash) with 2,000 ppm hydrazine caused slight temporary injury.
Concentrations of 6,000-10,000 pprn hydrazine caused increased injury
and some plants died. Fumigation of these and alfalfa seedlings with
25-30 ppm hydrazine caused severe injury including wilting, dehydra-
tion, and defoliation (Heck et al. , 1963).
10
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Effects On Humans
Data from human exposures to hydrazine are rare, but as early
as 1887 Curtius recognized that hydrazine vapors were extremely
irritating to the eyes, nose, and throat. Comstock et al. (1954),
citing a 1946 U.S. Naval Report, mention that exposure to hydrazine
vapor produces immediate and violent irritation of the nose and throat.
Over a period of hours itching, burning, and swelling of the eyes may
develop. After severe exposure, blindness, which lasts for about a
day, may ensue. Inhalation of hydrazine vapor causes dizziness and
nausea, and dermal contact with concentrated solutions of hydrazine
results in alkali-like burns (Krop,, 1954).
Olin Corporation, which produces anhydrous hydrazine and
hydrazine hydrate, has maintained records of its employees since
1953. During that time 57 persons worked in the plant; 22 are still
employed in the hydrazine. operation, 9 work somewhere else in the
same plant, and 7 others are employed at other company locations.
Only 4 deaths have occurred among the 57 employees and all were con-
sidered to be the result of natural causes. From 1953 through 1960
there were 21 exposu*.ep to hydrazine that required.medical attention.
The majority of these involved severe eye irritation from vapors;
the remainder involved primary skin irritation. One employee required
reassignment because of dermal sensitizatibn.
There are a number of published reports on dermal sensitization
arising from exposures to hydrazine hydrate (Evans, 1959; van Ketel,
1964; Hovding, 1967), or hydrazine hydrobromide (Cook, 1955; Wheeler
e^al^, 1965). It should be noted that the development of an allergy to
hydrazine or its salts may generate sensitivity to hydrazine derivatives,
including the drugs isoniazid and hydralazine (Apresoline). Use of
these drugs by sensitized persons produces extensive eczema.
Severe effects from human exposures to hydrazine hydrate also
have been noted. In 1965 Reid reported that a machinist became un-
conscious after drinking some concentrated hydrazine solution. The
victim remained unconscious for several days and experienced numerous
seizures during this time. However, his condition gradually improved
and he was discharged from the hospital after two weeks although he
still had residual neurological defects. His subsequent fate is unknown.
Sotaniemi_et al_, (1971) described another machinist who died, apparently
from repeated exposures to hydrazine hydrate. Initially, the victim
11
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had experienced nausea, tremor, and conjunctivitis every time he
handled hydrazine. On these occasions the hydrazine vapor co.ncentra -
tion was estimated at 0. 071 mg/m , but no details on the handling or
skin exposure were given. After six months of repeated exposures to
hydrazine he was admitted to the hospital because of cough, fever,
diarrhea, vomiting, icterus, and stupor. He was jaundiced and in-
coherent; his cardiac rhythm was irregular, his blood pressure was
100/70 mm Hg. , his abdomen was enlarged, and his liver was tender.
He died after 3 weeks and autopsy showed severe tracheitis and
bronchitis, lobar pneumonia, severe tubular necrosis with interstitial
hemorrhage and inflammation in the kidneys, small focal liver cell
necroses, and areas of granular degeneration of heart muscle fibers.
Treatment of Hydrazine Toxicity
Any material on the skin should be washed off immediately.-
Hydrazine is absorbed into the bloodstream very rapidly. Unfortunately,
there is no specific therapy.
Treatment is symptomatic, aimed at controlling convulsions,
overcoming hypoglycemia, and maintaining fluid balance and urinary
output. Clark et al. (1968) give a more detailed discussion of sup-
portive measures.
12
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Existing Air -Quality Standards
The Threshold Limit Value adopted by th<: ACGIH for 1973 is 1. 0
ppm (1. 3 mg/M ) with a "skin" notation. This value was based on
studies of Comstock et_ah_ (1954) who found no deaths amon™ dogs and
rats exposed to 5 ppm hydrazine, 6 hours daily, 5 days per week for 6
months. •
The Emergency Exposure Limits (EEL) recommended for
spacecraft operations by the Committee on Toxicology of the NAS/NRC
are 30 ppm for 10 minutes. 20 ppm for 30 minutes, and 10 ppm for 60
minutes. The 10-minute limit is less than 10% of the 4-hour LC Tor
-nice and rats found by Jacobson^t al. (1955). These limits are
deemed well below those necessary to produce significant metabolic or
CNS effects.
Proposed Short-Term Limits
The rationale for recommending limits for short-term exposure
of the public to air pollutants is detailed in the first document of this
series: "Basis vor Establishing Guides for Short-Term Exposures of
the Public to Air Pollutants," (NAS-NRC, 1971). These limits include
both Short-Term Public Limits and Public Emergency Limits.
Short-Term Public Limits (STPL's)
The limits for short-term exposure of the public to air pollutants
are established with a view toward the possibility of occasional repeated
events in the" same locality. These events, such as intentional release
of hydrazine to the atmosphere from firing of rocket motors, are
assumed to be controllable so that the limit is not exceeded in any area
occupied by the public.
The primary effects in animals from acute exposures to hydrazine
are pulmonary irritation, liver damage, and , at high doses, central-
nervous-system effects including convulsions. Similar effects have
been observed in humans with the addition of contact dermatisis and
dermal sensitization. None of the foregoing effects are anticipated at ,
the STPL's recommended since they are well below the lowest acute-
effect level observed in animals (19 ppm for 2 hours). These are all
time-weighted averages within the periods given. As a further
-------
precaution against pulmonary irritation the recommendation for 10
rninutes has been restricted to one half the total dose recommended
for 30 and 60 minutes.
STPL's
Time
10 min
30 min
60 min
Public Emergency Limits (PEL's)
Limit (25° C/760 mm Hg)
15 ppm (20 mg/m3)
10 ppm (13 mg/m3)
5 ppm ( 7 mg/m3)
Public emergency limits are those for accidental, unpredictable
or uncontrollable events. These exposures are expected to be single
events in the lifetimes of the very few people who would be accidentally
exposed. The PEL's assume that some temporary discomfort may
occur from irritation of the eyes and upper respiratory tract, but
that any effect resulting from the exposure is reversible .and without
residual damage. As a further precaution against pulmonary irritation
the recommendation for 10 minutes has been restricted to one-half the
total dose recommended for 30 and 60 minutes.
The PEL's for hydrazine are identical to the EEL's. They are
time-weighted averages.
PEL's
Time Limit (25° C/760 mm Hg)
'10 min ' 30 ppm (40 mg/m )
30 min . 20 ppm (25 mg/m3)
60 min 10 ppm (13 mg/m )
14
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III. GUIDE FOR MONOMETHYLHYDRAZINE
/
Background ' /
Monomethylhydrazine (MMH) is an important reactant in high-
energy propellant systems. It is used almost exclusively as a rocket
fuel and its consumption fluctuates with its use in our space program.
At the present time about 200. 000 pounds of MMH are produced
annually in the United States.
Physical and Chemical Properties . !
MMH is a vitriolic liquid that fumes in air and possesses a
characteristic ammoniacal odor. The compound has a great affinity
for water and mixes with it in all proportions to yield weakly basic
solutions (pKa 8. 0±. 1). It is only partially miscible with hydrocarbons
and low-molecular-weight alcohols. Chemically, MMH is notable for
its strong reductive capacity. In Jus respect MMH vapor is extremely
reactive and undergoes rapid autoxidation in air. Vernotje_t al. (1967)
'studied this reaction in ?ome detail since the rate of autoxidation
affects the stability of solutions of MMH exposed to air.
The autoxidation of MMH results in a variety of products in-
cluding carbon monoxide, methanol, acetaldehyde, and various carbon
or nitrogen heterocyclic compounds. It appears that molecular nitrogen
is the main product of the reaction and some methane is also produced.
Vernot jet_al^ (1967) have shown that the reaction obeys first-order
kinetics with respect to MMH and is probably surface catalyzed. They
have reported the half life of MMH vapor to be 34 minutes in a 320-ml
glass container at room temperature.
MMH has many properties that contribute to its desirability as a
fuel. The compound is extremely flammable and will ignite spontane-
ously if it comes in contact with metallic oxides or other oxidizing
agents, or even if it is exposed to air over a large surface area. Its
decomposition is highly exothermic yet the liquid itself is reasonably
easy to handle and store since it is stable up to its boiling point if kept
out of contact with air and it is not sensitive to decomposition from
shock or friction. Table 1 lists some of the physical constants of MMH.
15
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Acute Toxicity
MMH is an extremely lethal compound that exercises acute toxic
effects in the central nervous system. (CNS). The LD^Q values that
have been determined for MMH are summarized in Table 2 and LC^Q
values are shown in Table 3. MacEwen_eŁ ah (1969) conducted a series
of experiments to establish Emergency Exposure Limits. (EELs) for
MMH vapor. They exposed dogs, monkeys, rats, and mice to MMH
vapors for single periods of 15, 30, or 60 minutes at concentration that
would yield concentration x time (CT) doses of 900 ppm-minutes. The
900 ppm-minute CT dose of MMH used in these experir \ents was cal-
culated to be 25% of the maximum nonlethal concentrations for the most
susceptible species tested, the squirrel monkey. This concentration is
also below the lowest dose reported to cause marginal decrements in
the performance of trained monkeys (Reynolds and Back, 1966) and cats
(St carman et_ah , 1969a). None of these exposures produced respira-
tory irritation, overt signs of toxicity, biochemical, hematological, or
pathological abnormality in'any of the four species tested.
The signs of MMH toxicity in mice, rats, dogs, and monkeys in-
clude irritation of nose and eyes, salivation, emesis, diarrhea, hyper-
activity, tremors, and severe tonic-clonic convulsions, which cause
death.
When Ueynolds and Back (1966) injected 18 monkeys intraperi-
toneally with small amounts of MMH-(2. 5-5 mg/kg), 10 animals
showed decrements in t^e performance of previously learned operan*
tasks before the appearance of clinical evidence of illness; Sterman et
al. (1969b) have reported dose-related effects on the learned perfor-
mance of cnts given subconvulsive doses of MMH. Intraperitoneal •
injection of 1, 2, or 4 mg/kg MMH depressed the runway performance
of all cats within thirty minutes. Those cats receiving 1 to 2 mg/kg
showed smalj decrements in performance initially but, surprisingly,
performance was actually facilitated 24 hours after injection. However,
the performance of cats receiving 4 mg/kg was completely disrupted
at the end of 2-5 hours and was still depressed after 24 hours. Con-
vulsions were initiated in cats given 9 mg/kg, but it is interesting to
note that the onset of convulsions was delayed in cats who had been
trained to restrict their physical movements. • '
16
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Even though subtle changes in behavior can be detected before the
r*' convulsions, it has not yet been possible to identify a specific
neural site of action for MMH. At the present time it can only be said
that MMH acts somewhere in the ventral structures of the mid-brain
(Weir .ei.al^, 1965). The evidence for this assumption arises from ex-
periments of Witkin and Weatherby (1955), who showed that rats and
mice exposed to MMH in excess of ^D-- doses do not convulse caudal
to a cord transection or after prior treatment with d-tubocurarine. It
has also been shown that convulsions induced in mice and rats by MMH
. can be abolished by the administration, of secobarbital (50 mg/kg),
phenobarbital (100 mg/kg), or mesantoin (200 mg/kg). Pyridoxine
counteracts convulsive effects in several species (Back_e_t a_l_. , 19'i3b).
Acute exposure to MMH produces effects other than those on the
CNS. Sopher_et alj U967) have described toxicity in dogs that begins
with an episode of severe intravascular hemolysis, hemoglobinemia,
and hemoglobinuria. This is followed by nephrotoxicity, which may
include a frank necrosis of proximal tubular epithelial cells. Marked
erythrophagocytosis by the Kupffer cells of the liver also occurs after
'12 to 24 hours. Both the physical signs and pathology of the toxicity
increase as the dose of MMH increases from 10 to 30 mg/kg.
Comparable dose levels do net produce severe effects in monkeys.
The only renal effect these authors observed was swelling of the
proximal tubular epithelium. Massive doses of MMH do not produce
hemoglobinuria in monkeys and although erythrophagocytosis is seen
it is not especially prominent. Back and Pinkerton (1967) have reported
that intraperitoneal injections of MMH cause fatty infiltration of the
liver in monkeys. ' !
These hemolytic, renal, and hepatic effects are delayed and appear
to be dissociated from CNS effects since they are not suppressed by
pyridoxine (Sopher_et aU , 1967). They are not as pronounced when MMH
is administered by inhalation rather than injection and in.any event are
not.severe enough to cause death.
Repeated-Dose Toxicity
Back and Pinkerton (1967) investigated the effects of daily doses
of MMH repeatedly injected vntrapeiitoneally into monkeys, Their
observations indicate that small increments of 2-5 mg/kg change
"no-effect" doses of MMH to lethal doses. Twenty-three injections
17
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of 2. 5 mg/kg*over a five-week period produced virtually no signs of
illness in eight monkeys. However, successive daily injections of
5 mg/kg caused eight other monkeys to vomit on day two; four of the
eight vomited and two convulsed on day three. The daily dose was
then reduced to 2. 5 mg/kg for eight days and none of these animals
showed any adverse effects. Four received 12 more injections of 2. 5
mg/kg MMH without effect. The dose for the other four was increased
to 5 mg/kg/day and 12 such doses were tolerated with only occasional
emesis. Finally three monkeys were placed on a regimen of 7 mg/kg/
d5.y alternating with 10 mg/kg/day; one died on day two) one on day
three, and one on day four. These data also suggest that daily dosee
of 2. 5 mg/kg or 5 mg/kg MMH do not have cumulative lethal effects
since monkeys survived as many as 20 injections or a total dose of
65-95 mg/kg with no ill effects. However, the possibility that MMH
build-up can occur at other times cannot be excluded.
Metabolic and morphologic data were collected on all the animals
in these studies. The authors were not able to discover anatomical or
biochemical pathology at any dose level. .This finding is remarkable
in view of the .fact that extensive renal damage is s.een in dogs given a
single injection of 5-10 mg/kg MMH (Sophcr_et aL , 1967).
Chronic exposures of dogs and monkeys to low concentrations of
MMH vapor have been shown to produce a variety of hemolytic effects
that arc related to the reaction of MMH with circulating red blood
cells (MacEwen and Haun, 1971). Groups of 8 beagle dogs and 4 rhesus •
monkeys were exposed to 0. 2, 1. 0, 2. 0, and 5. 0 ppm MMH vapor for
six hours a day, five days a week for sic months. Half of the dogs
were killed at the end of the experiment while the others were held
for another 30 days to determine the reversibility of effects. A sig-
nificant number of dogs showed a sharp increase in reticulocyte
formation, serum bilirubin and alkaline phosphatase and a depression
of red cell count, hematocrit, and total hemoglobin. In those exposed
to 2 and 5 ppm the decrease in hemoglobin was accompanied by a dose-
related increase in methemoglobin formation and the 'production of
Heinz bodies. Hemolytic effects were not as pronounced in monkeys'
but red cell count, hematocrit, and total hemoglobin were decreased.
The pattern of methemoglobin formation in monkeys is not clear but
the appearance of Heinz bodies is taken as evidence that some reaction
18
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occurs between MMH and hemoglobin. Few detrimental effects were
observed during chronic exposures of groups of 50 Wistar rats and
40 ICR mice to 0. 2, 1. 0, 2. 0, and 5 ppm, 6 hours a day, 5 days a
week for 6 months. At concentrations of 2. 0 and 5 ppm some mice died
and some rats showed a dose-related depression of growth.
MacEwen and Haun (1971) concluded that chronic exposure of dogs
to MMH produces a dose-related hemolytic anemia with Heinz body
formation, which has no apparent threshold dose and which is rever-
sible after removal from exposure, at least up to 5 ppm. Because of
the similarity between dog and human blood, (Leahy, 1970) MacEwen
_e_t al. (1970) have recommended that the current Threshold Limit
Value (TLV) of 0. 2 ppm be re-examined to consider a safety factor for
individuals with pre-existing blood dyscrasias or hemolytic traits,
Tissue Pathology
Pathologic findings in most species exposed to lethal concen-
.•trations of MMH include pulmonary congestion with some hemorrhage,
hepatic congestion of varying degrees, and swelling of the renal tubular
epithelium, which frequently appears glassy and eosinophilic (MacEwen
et al. , 1969). Sub-arachnoid hemorrhage and spleens that are bloodless
with virtually empty sinusoids are frequently observed in dogs. Neither
the hemorrhage nor the visceral congestion are extensive enough to
cause death and they may be secondary to the severity of the convulsions
that precede death (Jacobson ct al. , 1955).
Visceral congestion is also apparent in dogs and monkeys that sur-
vive near-lethal exposures to MMH but it is not as severe as that seen
in animals that died during exposure. MacEwen et al. (1969) sacri-
ficed dogs and monkeys serially for 60 days after exposure to high con-
centrations of MMH. During and after exposure the most common and
persistent pathology occurs in the kidney and ranges from mild
swelling of the tubular epithelium to vacuolization and coagulative
necrosis of the epithelial cells. The renal changes observed in dogs
were more extensive than those seen in monkeys. :
Dogs exposed to subconvulsive doses of MMH exhibit hematuria,
hemoglobinuria, methemoglobinuria, and urinary cast formation
(Sopher_et_aL , 19f>7). Histopathologic examination of their kidneys
reveals proteinaceous precipitates in the proximal tubules with
occasional hemoglobin casts and moderate to severe degeneration of
19
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the proximal tubules frequently accompanied by tubular necrosis.
Although renal function in monkeys does not appear to be greatly
affected by exposure to MMH, George_e_t ah (1968) have described some
subcellular morphologic kidney changes after single injections of 7. 5
mg/kg or repeated injections of 2. 5 or 5 mg/kg MMH.
Kroe (1971) found renal tubular hemosiderosis in dogs and mice
exposed intermittently to MMH vapor in concentrations greater than 1
ppm for six months. He also observed poriportal cholestasis, bile-
duct proliferation and hemosiderosis in the livers of both species.
These effects were not seen in monkeys or rats.
Absorption, Distribution, and Elimination
MMH can be detected in plasma shortly after 1. p. injection
(Pinkerton .e^al^, 1967) or cutaneous application (Smith and Clark,
1969); peak plasma levels generally occur after 2-4 hours. Distribu-
tion studies at 2 and 4 hours have shown that large amounts of MMH
appear in muscle and that relatively high concentrations are found in
•the liver, kidney, bladder, pancreas, and serum of mice, rats, dogs,
and monkeys. The elimination of MMH or its metabolites occurs via
both urine and respiratory gases. Pinkerton j?Ł a_h (1967) found that
25-40% of MMH or its metabolites was excreted in urine after 48 hours.
In the mammalian kidney MMH is excreted by a combination of glo-
merular filtration, passive diffusion-mediated reabsorption and
simultaneous tubular secretion, (Coe_eta_l_., 1967). Dost_etal_. (1966)
showed that MMH is initially expired by rats as 4 parts methane and 1
part CO?. The mechanisms involved in the production of CO and CH
from MMH are not known but rate studies suggest that the two gases
may be produced by different mechanisms.
The respiratory and urinary elimination of MMH appears to be
subject to species variations and dose-related effects. The data of
Pinkerton_eŁ ah (1967) indicate that mice, rats, dogs, and monkeys
probably clear MMH in different ways. Dogs do not attain maximum
excretory rates or tissue levels until four hours .after injection, while
monkeys, rats, and mice reach maximum levels within two hours.
This difference may explain the renal side effects from administration
of MMH that occur in dogs but not in other species. Dost et al. (1966)
observed that the fraction of MMH converted to respiratory gases was
dependent on the dose. After 27 hours 80% of a 0. 46 mg/kg dose, 37%
of a 5, 5 mg/kg dose, 31. 0% of an 11 mg/kg dose, and 24. 0% of a 22
mg/kg dose were converted to methane and carbon dioxide. Similar
20
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reductions in urinary elimination of increased doses of MMH also
occurred. After 27 hours rats excreted 40% of a 5. 5 or 11 mg/kg dose but
only 20% of a 22 mg/kg dose. The lower rate of combined respiratory
and urinary elimination of higher doses was accompanied by a greater
retention of MMH in tissue. The authors speculated that .thero may be
a limit to the rate at which the compound can be excreted. However,
these effects could also arise, from failure of excretory mecharisms
due to intoxication.
Effects on Metabolism and Enzymes
Present evidence concerning the effects of alkylhydrazines on
carbohydrate metabolism is inconsistent. However, attempts are being
made to clarify this matter because these effects may be associated with
some of the regulatory mechanisms that influence insulin secretion.
The factors that mediate insulin release are not well understood but
many effects of MMH toxicity appear to resemble those of insulin in-
sufficiency.
In 1964 O'Brien_et a_l. found that acute LD doses of MMH given
to fed rats caused hyperglycemia, which occurred immediately and
lasted several hours. Later Fortney and Clark (1967) reported the oc-
currence of transient hypoglycemia and glycogen depletion in anesthetized
dogs given acute doses of MMH. Monkeys given acute doses of 30
mg/kg MMH also showed severely depressed glucose levels within an
hour after injection (Back and. Thomas, 1970).
Recently, DostŁt_aJ_._ (1973) have observed that it is difficult to
distinguish specific effects of high doses of MMH from the general
physiologic damage of massive intoxication. They conducted carefully
controlled studies on rats by a method of continuous glucose infusion,
which allowed observations of the early effects of lower doses, the in-
creasing effect of accumulating material, the nature of acute toxic
episodes and recovery, if it occurred. They found that subacute doses
of MMH caused spectacular increases in the blood glucose of fasted
animals given an adequate glucose supply and substantial increases in
fasted rats given no glycogen or glucose. The administration of 0.05 ,
mMole/kg/hr MMH to fasted rats who had been receiving a continuous
infusion of 150 mg/hr glucose-6- C for 10 hours produced an increase
in blood glucose that started three hours after MMH was added to the
infusion. Blood glucose rose steadily thereafter from a concentration
21
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of about 80 mg/100 cc to 170 mg/100 cc. The MMH infusion was stopped
after 7 hours because of convulsions but blood glucose continued to
rise for another hour, reaching a peak of 280-290 m'g/100 ml and
remaining elevated for four hours. P'reconvulsive behavior was
evident about two hours after blood glucose had obviously begun to
rise and an hour before the onset of convulsions. Rats fasted for 36
hours were given a three-hour infusion of 0.1 mMole/kg/hr MMH with
only trace amounts of added glucose, Blood glucose increased from
about 75 mg/100 ml to 85 mg/100 ml blood. At this point convulsions
ensued. The MMH infusion was stopped, but blood glucose rose
sharply to about 130 mg/100 ml blood. The investigators also found
that crystalline insulin added near the peak of increased blood glucose
reversed the hyperglycemia. It caused a brief but precipitous drop
in blood glucose, which recurred when the dose of insulin was re-
peated.
While blood glucose levels were increased by the administration
of MMH the oxidation of glucose to CO? was expressed in both fasted
rats and those with adequate glucose supply. • It ic interesting to note
that the output of respiratory CO, returns to normal at the end of MMH
administration when glucose infusion precedes the infusion of MMH but
not when infusion of MMH precedes the administration of glucose.
When pyridoxine is administered after MMH the oxidation of
glucose to respiratory CO2 is increased and blood glucose levels
decline to normal (Dost e^al^, 1973). Pyridoxine also decreases MMH
inhibition of glutamic and dihydroxyphenylalanine (DOPA)decarboxy-
lases and glutamic-pyruvic transaminase in mouse brain (Furst et al. ,
1968). These findings lead to the speculation that the central nervous
system effects of MMH may be related to these metabolic processes
because they are all affected by the administration of pyridoxine.
However, this cannot be established from the information that is
available.
Cardiovascular and Renal Effects . .
The cardiovascular response to MMH in both conscious and uncon-
scious dogs is characterized by depressor effects. Weir et al. ,
(1965) measured changes in the cardiovascular function of two con-
scious dogs initially anesthetized with 25 mg/kg i. v. of sodium
thiopental that received 25 and 50 mg/kg MMH, respectively, and
four unconscious dogs (30 mg/kg sodium pentobarbital t. v. ) that
received 25 mg/kg (one dog), 50 mg/kg (two dogs) and 100 mg/ke
(one dog). In all instances the MMH was given by intraperitoneal
22
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injection. In all cases the MMH caused cardiac slowing accompanied
by a-minor fall in blood pressure in which the systolic pressure de-
creased about twenty minutes after injection and the diastolic pressure
after ninety minutes. Recovery from these effects was still not com-
plete after four hours. These authors also showed that MMH does not
depress blood pressure or alter cardiac rate in animals in which gangli-
onic blockade had been produced with hexamethonium. Fifty mg/kg
MMH administered in two dogs treated with 2 mg/kg hexamethonium
produced a 25-30 mm rise in systolic and diastolic pressure and no
alteration in cardiac rate. These findings support the conclusion that
the cardiac slowing that usually occurs after the administration of MMH
may be ascribed to medullary stimulation (Weir et al. , 1965).
Experiments were also conducted to study the effect of MMH on
the pressor activity of tyramine (Weir_e_t al. 1965). When 50 ring/kg
was given to two anesthetized dogs the pressor effect of tyramine in-
creased 35% and the duration of the response doubled. These effects
appeared within thirty (30) minutes and persisted for two hours. The
pressor response to norepinephrine was unaltered by MMH. The
prolongation and intensification of the cardiovascular effects of
tyramine is generally accepted as evidence for monoamine oxidase
inhibition; therefore, these experiments are consistent with other
demonscrations that MMH is an inhibitor of this enzyme.
Carcinogenicity . ••
Toth and Shimizu (1973) recently reported that significant numbers
of Syrian golden hamsters developed malignant histiocytomas of the
liver after ingesting 0. 01% monomethylhydrazine in drinking water
during their lifetime. Solutions were made up fresh on Monday,
Wednesday, and Friday of each week; pH was not controlled (Toth,
1973). This Kupffer cell sarcoma occurred in 43 of 100 animals. The
first tumors were observed after 46 weeks and the last developed after
103 weeks; the average latent period was 75 weeks. The average daily
intake of MMH was 16 mg/kg based on a water consumption of 184 ml/
kg/day. Convulsions arid possibly anemia were noted at this dose level
(Toth, 1973). No tumors were observed in control groups that ingested
drinking water not treated with MMH.
Therapy of Intoxication
Some protection from the toxic manifestations of MMH can be
attained. Mice and rats poisoned with 2 x L-DSQ of MMH may be kept
free of seizures by repeated administration of mesantoin, phenobarbital,
23
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or secobarbital but convulsions in dogs poisoned with MMH were not
controlled by large doses (6 mg/kg) of mesantoin. Secobarbital did
control convulsions in dogs, but 5-6 hours after the administration of
MMH the dogs became comatose (Medical College of Virginia, 1954).
Backjet aJL (1963b) and Geake et_aJL (1966) have shown that pyridoxine
can counteract the convulsive effects of MMH in several species.
However, pyridoxino does not fully prevent hypoglycemia, which may
occur after the administration of large doses of MMH. Monkeys givtn
30 mg/kg MMH required additional glucose as well as pyridoxine to
survive (Back and Thomas, 1970).
Effects on Humans
Reliable data on accidental human exposures to MMH are not
available. Cases of eye irritation or skin irritation after repeated
exposures to the chemicals have been reported from a plant where
both MMH and UDMH are manufactured. In one instance dermal sen-
sitization was severe enough to require jot reassignment. The most
accurate information on human exposures to vapor has been obtained
from controlled studies done by MacEwen ej^al^ (1970), who exposed
seven volunteers to 90 ppm MMH for 10 minutes. Subjects found 90
ppm MMH more irritating to the eyes.and nose than 30 ppm NH^ but
considerably less irritating than 50 ppm NH-j. Most experienced a
slight moistening of the eyes but no overflow of tears. Several sub-
jects reported a slight tickling sensation of the nose but none exper-
ienced coughing of bronchospasm. There were no changes in any of
fourteen clinical chemistry tests that were followed for sixty days
after exposure, but Heinz bodies amounting to 3-5% of the erythrocytes
appeared in the exposed subjects by the seventh day. The Heinz bodies
were not accompanied by any signs of anemia or reticulocytosis.
Heinz body formation began to decline after two weeks and none were
present at 60 days after exposure. Spirometric measurements of
pulmonary function made over the 60 day period showed no changes in
six subjects. One subject had decreased function but also displayed
symptoms of respiratory infection. A chest X-ray showed acute
bronchitis in the lower left lung field. This condition cleared in seven
days and the pulmonary function measurements returned to baseline
values.
Existing Air-Quality Values
Threshold Limit Value (TLV)
The American Conference of Governmental Industrial Hygienists
(1973) has established a Threshold Limit Value (TLV) of 0.2 ppm by
24
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volume of MMH vapor in air for industrial exposures. This is intended
to be a concentration to which nearly all workers may be repeatedly
exposed day after day without adverse effect.
Emergency Exposure Limits (EEL's)
The Committee on Toxicology of the National Academy of
Sciences-National Research Council has recommended the following
Emergency Exposure Limits for MMH for military and space personnel:
90 ppm for 10 minutes; 30 ppm for 30 minutes; and 15 ppm for 60 minutes.
Proposed Short-Term Limits
Experimental data and experience indicate that man is susceptible
to irritation and possible injury from exposure to MMH. Concentrations
up to 90 ppm cause some irritation of the eyes and respiratory tract
but short exposures at this level are not incapacitating and would not
interfere with self-rescue. Repeated exposures to low concentrations
of MMH can result in chronic hemolytic anemia. Any exposure to high
concentrations of MMH would probably result in convulsions. The
short-term limits for the exposure of the public to air pollutants have
been set as described in the first document of this series, "Basis for
Establishing Guides for Short-Term Exposures of the Public to Air
Pollutants", NAS-NRC (1971).
Short-Term Public Limits (STPL's) •
The limits for short-term exposure of the public to air pollutants
are established in view of occasional repeated events in the same
locality. Those events, such as the intentional release of MMH to the
atmosphere, are assumed to be controllable with respect to concen- ;
tration and duration of release so that the limit is not exceeded. The
exposure limits selected for STPL's are one-tenth of the levels known
to produce minimal effects in man which are fully reversible. No
adverse effects to health are anticipated at these levels. The STPL's
are time-weighted averages for the periods indicated.
STPL's
TIME LIMIT (25°C/760 MM. Hg)
10 min 9 ppm (16. 9 mg/m3)
30 min 3 ppm (5. 6 mg/m3)
60 min 1. 5 ppm (2. 8 mg/m^)
25
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Public Emergency Limits (PEL's)
Public Emergency Limits (PEL's) are applicable to accidental,
unpredictable, or uncontrollable exposures of the public to toxic
substances. These exposures are expected to be single events in
the lifetimes of the very few people who would be accidentally exposed.
The PEL assumes that some temporary discomfort may accrue to the
public but that any effect resulting from the exposure is reversible and
without residual damage. The limits recommended in this report are
based on studies (MacEwen_et ah , 1969) that indicate no adverse effects
on dogs, monkeys, rats, and mice exposed to a 900 ppm-minute CT
dose of MMH. Exposure of humans to 90 ppm MMH for 10 minutes re-
sulted in the formation of some Heinz bodies in the blood, but the effect
was slight and reversible (MacEwen_eŁ aJL , 1970). This effect is con-
sidered acceptable in the rare event of an emergency. These values
are considered to be time-weighted averages.
PEL's
TIME LIMIT
LIMIT
90 ppm (169 rng/m3)
ju mm 30 ppm (56 mg/m^)
60 min 15 ppm (Z8 mg/m )
10 min
30 min
26
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IV. GUIDE FOR 1,1-DIMETHYLHYDRAZINE
Background
At the present time 1,1-dimethylhydrazine (unsymmetrical
dimethylhydrazine, UDMH, Dimazine) is manufactured almost ex-
clusively for rocket fuels, in which it is used either as the single
high-energy component or as an ingredient in mixed arnine fuels.
About 1-2 million pounds are produced annually for this purpose.
UDMH is assuming increased importance as a synthetic intermediate
but the extent of this use is not known at the present time.
Physical and Chemical Properties
UDMH is a colorless, oily, hydroscopic liquid that fumes in air
with an ammoniacal of "fishy" odor. The compound has a high vapor
pressure and is extremely volatile. Its vapors are oxidized slowly
and exothermically in air at room temperature. UDMH is a powerful
reducing agent and reacts with a variety of reagents. It is completely
miscible with water, alcohol, diethylenetriamine, hydrazine, and most
hydrocarbons. It is a weak base (pK 7. 21) that reacts exothermically
with water to form weakly alkaline solutions which deteriorate on
standing in air.
UDMH is not sensitive to shock or fraction and is thermally stable.
However, the compound is flammable in air over a wide range of con-
centrations and is hypergolic with oxidants like hydrogen peroxide or
nitrogen tetroxide. It will ignite spontaneously if it is adsorbed on
materials with a large surface area or stored under conditions that
prevent the dissipation of heat that accumulates during air oxidation.
Table 1 lists some of its important physical properties.
-------
Effects on Animals
Acute Toxicity
UDMH is primarily a convulsant and a respiratory irritant (Back
_et al., 1963a; Back and Thomas, 1963). Regardless Of the route by
which it is administered, lethal intoxication with UDMH in the mouse,
rat, dog, and monkey usually progresses through tonic-clonic convul-
sions to respiratory arrest (Back and Thomas, 1963). Prior to con-
vulsions animals other than rodents may salivate and vomit. All
species show a time lapse between exposure to UDMH and the onset
of seizures, but what occurs in this interval is not known. Back and
Thomas (1963) have shown that the onset of seizures and death is
hastened by pretreatment of mice with pentylenetetrazol (Metrazol )
but UDMH does not alter the pentobarbital sleep time of mice. Con-
vulsive doses of UDMH produce significant dose-related alterations
in brain electrical activity, sensory and motor excitability, and per-
formance in a learned motor task (Fairchild and Sterman, 1964).
.Reynolds j?t aJL (1963) have found that substantial decrements in per-
formance appear soon after any exposure, which results in intoxication
that can be clinically observed in monkeys. Delayed death from other
than central nervous system effects has not been observed, but animals
surviving acute exposures may be either highly irritable or depressed
for several days.
LiDgQ data for all routes of administration except inhalation are
presented in Table 2. Dogs and monkeys appear to be more suscep-
tible to i. p. administration of UDMH than rodents. Witkin . (1956) found
the lethality of UDMH greater in rats than mice by i. p. , i. v. , and oral
routes. However, other observations (Back and Thomas, 1963; O'Brien
_et aL , 1964) indicate approximately the same LD values for both
species by i. v. or i. p. administration. The lethality UDMH on cutane-
ous application is considerably reduced because a large percentage of
the compound vaporizes before it is absorbed (Smith and Clark, 1971).
Jacobson_ejt aj_. (1955) determined the 4-hour LC of UDMH vapor
to be 172 ppm for mice, 252 ppm for rats, and 392 ppm for hamsters.
Weeks .e^al^ (1963) reported LC5Q values for rats to be 1,410 ppin for
one hour, 4,010 ppm for 30 minutes, 8,230 ppm for 15 minutes, and
24, 500 ppm for five minutes. These authors made log-log plots of
concentration vs. time for the LC^Q values and concluded that within
the span of their studies the lethality of UDMH was directly dependent
on the total dose.
28
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The L.C -values reported for dogs are 981 ppm for one hour,
.3, 578 ppm for 15 minutes, and 22, 550 ppm at five minutes (Weeks
.ejLaL.' 1963). In the same study it was found that dogs showed minimal
toxic responses (dullness, mild fasciculations, and slight tremors)
after exposure to 1, 200 ppm, 400 and 100 ppm for 5, 15, and 60 minutes
respectively. No adverse effects were seen in dogs exposed to 50, 200
and 600 ppm UDMH vapor for 60, 15, and 5 minutes respectively.
Jacobson et al. (1955) did not determine an LC^Q for dogs but found that
after exposure of 3 dogs for 192 minutes to 111 ppm, 2 dogs were dead
and the third moribund. He also reported that exposure of another
group to 24 ppm UDMH vapor for 4 hours had no effect on two of three
dogs but the other vomited, convulsed, and subsequently recovered.
Toxicity of Repeated Doses
The lethality of UDMH may be increased by repeated exposures to
the compound. The LD^Q for single doses administered i. p. to rats is
between 102-131 mg/kg (Table 2) yet Cornish and Hartung (1969) have
found that repeated injections of 70, 50, or 30 mg/kg resulted in a high
mortality rate among rats: 9 of 10 receiving 70 mg/kg/day died during
the first two days; 6 of 10-receiving 50 mg/kg/day and 5 of 10 receiving
3*0 mg/kg/day died during days two and three. These findings suggest
that UDMH is accumulated. However, this process is apparently limi-
•ted in some manner since all deaths occurred during the first three days
and the 10 of 30 rats that survived after three days also survived three
weeks of repeated administration of UDMH.
Other studies of repeated exposures to UDMH vapor (Rinehart et
al. , 1960) also suggest some accumulation of the compound in rodents
and dogs. The 4-hour LC^Q for mice has been reported as 172 ppm
(Jacobspn_et al. , 1955) but after exposure to 140 ppm for 6 hours a day
29 of 30 mice died in a calculated median survival time of three days.
Exposure to 75 ppm for five hours a day for seven weeks killed eight
of 30 mice within five weeks. The mice showed intermittent tremors
during exposure and all deaths resulted from clonic-tonic convulsions.
Although Jacobson_et al. (1955) found no deaths in dogs exposed to
25 ppm UDMH vapor for four hours, Rinehart Łt_al^ (1960) observed
severe toxic"signs and death in one dog after exposure to 25 ppm six
hours a day for three days. At this time he also reported severe
toxic signs (depression, salivation, emesis, diarrhea, bradycardia.
fever and convulsions) in one dog and minimal toxic signs (depression
and salivation) in another. However, both of these dogs survived 13
weeks of daily exposure to 25 ppm. All three dogs, including the one
that died, developed hemolytic anemia. Rinehart e^al^ (1960) observed
29
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only mild anemia in dogs exposed to 5 ppm six hours a day, 5 days a
week for 26 weeks. . . • .
On the other hand, it has been shown that repeated exposures to
small amounts of UDMH can occur without toxicity. Weeks et al.
(1963) observed no adverse effects in groups of four dogs exposed twice
weekly for six weeks to 50, 200 and 600 ppm UDMH vapor for 60, 15,
and 5 minutes respectively. Likewise House (1964) observed virtually
•no effects after the continuous'exposure of monkeys, rats and mice to
0. 56 ppm UDMH vapor for 90 days. Clinical chemistry determinations
were within normal limits and functional evaluations disclosed only a
decreased swimtime for rats and mice. However, some tissue
pathology did occur.
Cornish and Hartung (1969) found no fatalities among rats receiving
10 mg/kg/day i. p. for three weeks. This last finding confirmed prior
studies of Back and Thomas (1963) who found, in addition, no significant
differences between the acute lethality (LD^) of UDMH administered to
rats previously treated with 10 mg/kg UDMH for 20 days and the I'D5Q
for control animals.
Tissue Pathology
Neither Jacobson Łt_al^ (1955) nor Weeks Łt_aL. (1963) found any
pathology attributable to UDMH vapor in rats and dogs after single
lethal or non-lethal exposures. Rinehart_et al_. (I960) found no abnormal
morphology in rats and mice sacrificed at inter/als through a six-week
series or exposures to 140 ppm or 75 ppm UDMH vapor. However, dogs
exposed daily to 25 ppm vapor for several weeks had pigment deposits in
the spleen and in the Kupffer cells of the liver; one dog developed al-
veolar hemorrhage, emphysema, and atelectasis. House (1964) exposed
animals continuously to 0. 56 ppm UDMH for 90 days and found that liver
hemosiderosis appeared in mice; rats showed renal tubular vacuolization
and necrotic areas in the heart while monkeys acquired some degenera-
tive lesions in the liver, probably fatty changes. Repeated doses of 10
mg/kg UDMH i. p, produced no significant pathologic changes in rats
(Back and Thomas, 1963; Cornish and Hartung, 1969). However, rats
surviving 50 mg/kg or 70 mg/kg i. p. for 21 days had slight fatty changes
in the renal tubular epithelium (Cornish and Hartung, 1969). Recently,
it has been shown that turkeys given feed previously treated with UDMH
developed fatty metamorphosis of hepgitic cells. Ultrastructural studies
showed that the lipid congregates in glycogen areas and is associated
with a dis-tended smooth endoplasmic reticulum (Simpson and Barrow,
1972K
30
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Adsorption, Distribution, and Elimination
Regardless of the route of administration, UDMH is rapidly absorbed
into the blood and excreted by the kidneys. UDMH was detected in
the blood within 30 seconds after the application of 300 - 1,800 mg/kg
to the shaved skin of dogs (Smith and Clark, 1971) but peak concentra-
tions did not appear for 60 - 201 minutes. Back_e_t al. (19.63a) found
that peak concentrations of UDMH in plasma occurred 15-60 minutes
after the intraperitoneal administration of 50 mg/kg to hydrated rats,
cats, dogs, and monkeys. UDMH could be detected in the urine of
these animals three minutes after injection and both radiometric and
colorimetric techniques indicated that 30-50% of the dcse was excreted
within five hours. Dost_et a_L (1966) also measured the urinary secre-
tion of UDMH and found the amount of 14C in the urine 53 hours after
the intraperitoneal administration of UDMH-14C to be equivalent to 56%
of a ZO mg/kg dose, 53% of a 60 mg/kg dose, and 70% of an 80 mg/kg
dose. In addition, these investigators showed that UDMH is meta-
bolized to respiratory CO^. • The latter process is apparently influenced
•by the amount of the compound given; in ten hours 30% of an 0. 88 m^/kg
dose, 15. 2% of a 20 mg/kg dose, and 7% of an 80 mg/kg dose were
metabolized to CC^-
Otherwise, very little is known a.bout the metabolism of UDMH.
Back jet_al. (1963a) have postulated that UDMH may undergo some
complexing in plasma, but distribution studies do not show the prefer-
ential accumulation of the compound in any tissue or organ. Aldrich
and Mitz (1963) found evidence for two metabolites of UDMH in urine.
They recovered 20% of a 40 mg/kg dose of l^C-UDMH from the urine
of rats and dogs within four hours. Fifty percent of this was unreacted
UDMH, 3-10% was identified as glucose dimethylhydrazone, and 20-25%
was a single component that was not identified but thought to be a
neutral hydrazone or hydrazide of higher molecular weight than pyruvic
acid.
Effects on Metabolism and Enzyme^ ,
An extensive array of metabolic and biochemical parameters' has
been investigated in an effort to understand the toxic actions of UDMH.
With regard to glucose metabolism, the injection of non-fasted rats with
LDjQ doses of UDMH caused marked hyperglycemia, which persisted
for at least an hour (O'Brien et al. , 1964), Similar hyperglycemia in
31
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anaesthetized dogs did not result in depletion of liver or muscle
glycogen (Clarkj:t ah , 1968) but Minard_e_t al. (1965) have reported that
convulsions induced by UDMH lowered brain glycogen levels in rats
and they concluded this resulted from the convulsion rather than a
direct action of UDMH. Amenta and Dominguez (1965) found that the in-
jection of 1. 25 mMole/kg UDMH inhibits the conversion of D-glucose-U-
*^C to 14cOj> but did not alter the production of respiratory CO^ from
acetate.
The pronounced central nervous system effects of UDMH intoxica-
tion have suggested some interference with amine metabolism. Reed
_et al. (1964) found that as little as 6 mg/kg UDMH administered intra-
peritoneally to rats inhibits the oxidation of methylamine-^C and put-
recine-l;4-*'*C to "CO^. UDMH also suppresses monoamine and
diamine oxidase activity (Reed_et al. , 19fa4) and produces severe
inhibition of glutamic acid-decarboxylace (GAD) activity but is only a
•weak inhibitor of Gamma aminobutyric acid (GABA) transaminase
(Medina, 1963). Medina (1963) also observed that subcutaneous in-
jection of 1. 25 mMole/kg UDMH depresses the conversion of glycine-1-
"C to respiratory ** CC>2 in intact rats while Reed_ŁŁal1 (1964) found
that intoxication of rats with 1. 5 mMole/ke UDMH i. p. did not decrease
the metabolism of sodium L-glutamate 1- C (4. 4 mMole/kg i. p. or 20
mMole/kg, oral) to respiratory CO... At the present time it is dif-
ficult to assess the significance of these observations.
Cardiovascular and Renal Effects
The intravenous injection of 1 to 50 mg/kg UDMH did not produce
any acute effect on the carotid blood pressure, respiration or ECG of
anaesthetized dogs (Back and Thomas, 1963b; Britz, 1965). It did not
alter responses caused by electrical stimulation of the peripheral end
of the cut vagus, nor did it affect the action of acetylcholine, histamine,
epinephrine, norepinephrine, or reserpine on blood pressure. All
animals given 100 mg/kg or more UDMH died in cardiovascular collapse
even though respiration was supported artificially (Back and Thomas,
(1963b).
UDMH produces a marked diuresis in rats. A single i. p. injection
of 80 mg/kg produced a three-fold increase in urine during a six-hour
period (Cornish ei_a\. , 1965; Barth^jil. , 1967). During the first two
hours after the injection the average urinary excretion of potassiur->. and
calcium was significantly less than normal (Barth Łt_al_. , 1967). On the
other hand Wong (1966) observed no appreciable effect on maximal
tubular readsorption of glucose and only a slight increase in glomerular
filtration rate after the injection of 45 mg/kg UDMH in dogs. Van Stee
(1965) also found no significant impairment of glomerular filtration rate:
and did not see any alteration in p-amino-hippurate and inulin clearances
in dogs. Repeated injections of 30-50 mg/kg daily for three weeks
32
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produced a marked water diuresis in rats that was sustained for the
entire period (Cornish and Hartung, 1969).
Carcinogenic ity
Argus and Hoch-Ligeti (1961) reported no increase in incidence of
tumors among 25 rats after gastric intubation of 0. 325 mg of UDMH
daily, 5 days per week, for 53 weeks; On the other hana. Roe et al.
(1967) found a significant increase in pulmonary tumors among 9 female
Swiss mice that survived more than 50 weeks of oral administration, 5
days per week, of 0. 5 mg/kg of UDMH. The tumors were of a type
that commonly arise spontaneously in mice.
Mutagenesis
UDMK reacts in vitro under severe conditions with the pyrimidine
bases in nucleotides to form dihydro- or 4-hydrazino derivatives or to
effect scission of the pyrimidine ring (Lingens and Schneider-Bernloehr,
•1965). The occurrence of similar reactions in vivo could alter the base
sequence in DNA or RNA and produce a mutagenic effect. Some muta-
genic effects of UDMH have been observed in bacteria but there have
been no similar observations in animals (Clark jet_aL_, 1968).
Therapy of Intoxication
UDMH is one of a group of carbonyl reagents, compounds charac-
terized by their ability to condense with the oxygen of aldehydes and
ketones, which may produce acute vitamin B^ deficiency and convulsions.
Experiments have shown that the convulsant activity of these agents can
be blocked by the administration of B, vitamins (Reeves. 196i; Vilter,
19t>4). Subsequently, Back et al. (1963b) found that pyridoxine was more
effective than- pyridoxamine in preventing UDMH convulsions in mice and
monkeys. On the basis of his data he suggested the administration of
25 mg/kg pyridoxine hydrochloi-ide for the emergency treatment of human
intoxication with UDMH. Half this amount would be given intravenously
and the remainder injected intramuscularly in several sites.
33
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Effects on Humans
Cases of human poisoning by UDMH have been rare. Shook and
Cowart (1957) refer to one event in which two workers 750 yards from
a spill of UDMH inhaled fumes and experienced initial choking and
difficulty in breathing. Four hours later both men became nauseated
and vomited but both recovered without further incidents. These
authors also reviewed the history of five people who had repeated lab-
oratory exposure to UDMH and six workmen engaged in storage and
transfer of the compound. None of these subjects had any acute signs
of toxicity. Evidence from other sources also lead these authors to
suspect that hemolysis develops after repeated exposures to UDMH.
Frierson (1965) has reported on six men who inhaled Aerozine-50
(AZ50), a 1:1 mixture by weight of hydrazine and UDMH. Because the
vapor pressure of UDMH is approximately 10 times that of hydrazine.
Aerozine vapor is approximately 85% UDMH (Azar_et ah , 1970). Four
men who had to work for two hours in an area contaminated with AZ50
suffered severe nausea and vomiting even though they were wearing
air packs and acid suits.' Two hundred mg of pyridoxine stopped emesis
within 20 minutes. Two other men were exposed to large amounts of
AZ50 vapor, one through a defective mask over a period of 90 minutes,
the other by direct inhalation. They complained of headache, nausea,
shakiness, burning sensation in facial skin, sore throat, and tightness
in the chest. Examination showed paleness, sweating, wheezing,
twitching of the extremities and clonic movements. Dyspnea and other
symptoms abated after the administration of 600 mg pyridoxine, 200 mg
i. v. , and 400 i.m. at two sites. However, both patients developed
pulmonary edema which subsided about six hours after the administra-
tion of steroiJs and oxygen. Follow-up studies over the next three weeks
revealed no abnormality in blood, liver or kidney function. Chest X-rays
taken four weeks later were normal.
Effects on Plants
UDMH has adverse effects on some seeds and plants. Heck et al.
(1963) found that 1, 000 ppm UDMH in water decreased the number of
squash seeds that would germinate. Hoover_et . _a_l. (1964) found that
concentration of UDMH less than 200 ppim did not affect the germination
of rice, Alaska peas, alfalfa, or endive but did inhibit the growth of all
plants except Alaska peas. Pinto beans and cotton seedlings grown in
solution containing UDMH showed dehydration and defoliation. When
UDMH concentrations reached 1,000 ppm cotton seedlings died in 48
hours. Seedlings (cotton, pinto bean, soybean, endive, squash)
sprayed with 2,000 ppm UDMH suffered slight temporary injury; those
sprayed with 6, 000 to 10, 000 ppm UDMH had increased injury and some
died. Fumigation of the seedlings mentioned above and alfalfa with
34
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25-30 ppm caused severe injury.
Existing Air Quality Values
Threshold Limit Value (TLV)
The American Conference of Governmental Industrial Hygienists
(1973) has established a Threshold Limit Value of 0. 5 ppm by volume
of UDMH vapor in air for industrial exposures. This is intended to be
a concentration to which nearly all workers may be exposed day after
day without adverse effect.
Emergency Exposure Limits (EELs) •
The Committee on Toxicology of the National Academy of
Sciences-National Research Council has recommended the following
Emergency Exposure Limits for UDMH for military and space personnel:
100 ppm for 10 minutes; 50 ppm for 30 minutes; and 30 ppm for 60
minutes.
Proposed Short-Term Limits
The philosophy underlying the recommendation of limits for short-
term and emergency exposure of the public to air pollutants is detailed
in the first document of this series: "Basis for Establishing Guides for
Short-Term Exposures of the Public to Air Pollutants", NAS-NRC (1971).
The few human exposures to UDMH that have occurred have been
accidental and to unknown concentrations. Such data are not adequate
for setting exposure limits. However, there is a large amount of data
from experimental exposure of animals and they suggest limits for
human exposures. The recommended total accumulated dose has been
reduced for both shorter exposure times in order to reduce the possi-
bility of exceeding the body's detoxification capacity and to minimize
any chance of respiratory irritation.
Short-Term Publyc Limits (STPL's)
The limits for short-term exposure of the public to air pollutants
are established in anticipation of occasionally repeated events in the •'
same locality. These events, involving intentional release of UDMH
to the atmosphere, are assumed to be controllable with respect to
-------
^
concentration and duration so that'the limit is not exceeded. The ex-
posure limits selected for STPL's are one-half the limits considered
acceptable for emergencies and arc well below the no-effect levels
for dogs, the most sensitive species (Weeks Łt_a_L , 1963). These are
time-weighted averages.
STPL's
Time Limit (25° C/760 mm Hg. )
10 min 50 ppm (127 mg/m3)
30 min 25 ppm (63. 5 mg/m3)
60 min 15 ppm (38. 2 mg/m3)
Public Emergency Limits
Public Emergency Limits are those for accidental, unpredictable,
or uncontrollable events. These exposures are expected to-be single
events in the lifetimes of the very few people who would be accidentally
exposed. The PEL assumes that some temporary discomfort may be
experienced by some individuals, but that any effect resulting from the
exposure is reversible and without residual damage. The following
time-concentration combinations have been selected because they are
below by a factor of 3 to 5 those that cause a detectable effect in dogs,
one of the most sensitive species. Weeks .et^aj^ (1963) found no adverse
effects in dogs exposed to 200 ppm for 15 minutes or 50 ppm for 60
minutes. They are time-weighted averages.
PEL's '
Time Limit (25° C/760 mm Hg)
10 min . 100. ppm (255 mg/m )
30 min 50 ppm (127 mg/m3)
60 min 30 ppm (76. 5 mg/m )
36
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Analytical Methods
Analytical methods for hydrazine as well as for monomethylhydra-
zine and unsymmetrical dimethylhydrazine are based on (1) coupling
to form colored compounds, (2) basicity of the compounds, (3) reductive
capacity of the compounds, (4) liberation of gas on reduction. None of
the methods is absolutely specific.
The coupling of hydrazine with p-dimethyl-aminobenzaldehyde to
forn: a yellow to orange azine can be used for quantitative determination
of hydrazine (Pesez and Petit, 1947). The procedure can be adapted
•for determination of hydrazine in a>ir by drawing a known volume of air
through an impinger containing two ml of concentrated hydrochloric
acid in 10 ml of water and then adding the coupling reagent to the
solution. Presumably, this reaction could also be employed to deter-
mine UDMH. A colorimetric method for UDMH ucing trisodium
pentacyanoamino ferroate as a reagent is suitable for analysis of
blood and urine (Pinkertonjet aj.. , 1961).
The quantitative method described by Geiger and Vernot (1967) for
determining monomethylhydrazine in air could be calibrated for hydra-
zine and UDMH; this method measures the change in absorbance of an
iodine-potassium iodide solution when, air containing hydrazine is passed
through it.
Hydrazine, MMI-I and UDMH can be measured quantitatively by
trapping their vapors in 3-5N hydrochloric acid, and then reacting this
solution with' potassium iodate. Nitrogen gas is released stoichio-
metrically iMcKennis jet_ aJL_f 1958).
The current flow between a reference electrode and a platinum
electrode at which hydrazine is oxidized can be calibrated to quantitate
concentrations of hydrazine vapor in air (Haller and Harshman, 1953).
The same oxidation reaction should be suitable for measurement of
other easily oxidizable hydrazine derivatives.
A detector kit for hydrazine and UDMH, for use with a hand-
operated sampling pump, is manufactured by Mine Safety Appliances
Company.
37
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A personal dosimeter for estimating exposure to the vapors of
hydrazine, MMH or UDMH can be made by impregnating a material
such as silica gel with "bindane" (A \,2' -bindane-l"3, 3' -trione)
aud spreading a thin layer of the impregnated material on a supporting
film base (Plantz_et a^. , 1968). Ammonia and cigarette smoke interfere
with this test system.
38
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Table 1
PHYSICAL CHEMICAL. PROPERTIES
Compound
Molecular Formula
Molecular Weight
Boiling Point°C
Melting Point°C
Odor Threshold ppm.
Density (25/25) g/cc.
Vapor Density (air = 1)
Vapor Pressure, mmHg(25 C)
Flash Point, °F(TCC)
Flammability Range in Air % Vol. ,
1 atm.
- 1 ppm Vapor, 25°C/760 mm
1 mg/1 vapor, 25°C/760 mm
Hydrazine
H2NNH
32.05
113.5
2.0
3-4
., 1.00
. 1.1
14. 38
100
4.7 - 100
0. 001309 mg/1
764 ppm
Monomethyl-
Hydrazine
CH HNNH
3 2
46.07
87.5
-20.9
1-3
0.87
. 1.6
49.63
80
2. 5 - 98
0.001881 mg/1 •
532 ppm
1,1, - Dimethyl -
Hydrazine
(CH3)2NNH
60.10
63.3
-58.0
0.3-1
0.78
2.0
157.0
5
' • *
2. 5 - 95
0.002554 mg/1
408 ppm
-39-
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Table 2
Acute Toxicity of Hydrazine, MMH and UDMH
(LD50)
Species
Mouse
Rat
•
Guinea Pig
Rabbit
Dog
Monkey
Route
Intravenous
Intraperitoneal
Oral
Intravenous
Intraperitoneal
Oral c
Cutaneous
Intravenous
Cutaneous
Intravenous
Intraperitoneal
LD50mg/kg
Hydrazine
57
62
59
55
59
. •
• . •
60
192
26
94
25
> 20
MMH
33
32
33
33
32
33
49
12
96
12
-
UDMH
250
290
132
125
265
119
104
102 •
131
122
1329
1060
60
60
1200
60 - 100
Reference \
Witkin, 1956
Witkin, 1956
Weir_et al. , 1964
Back and Thomas, 1963
1 Witkin, 1956
Witkin, 1956
Witkin, 1956
O'Brien et al_. , 1964
Witkin, 1956
Witkin, 1956
. Rothberg and Cope, 195.6
Rothberg and Cope, 1956
Rothberg and Cope, 1956
Witkin, 1956
Witkin, 1956
Patrick and Back, 196E
-40-
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Table 3
Acute Inhalation Toxicity of Hydrazine, MMH and UDMH
Species
Mouse
Rat
•
.•
Hamster
Dog
Monkey
^squirrel)
Monkey
(rhesus)
' Duration
of Exposure(hrs)
1
4
1/12
1/4
1/2
1
1
1
4
4
1/12
1/4
1
1
1
Hydrazine
254 :
640
58
MMH
122
56
65
244
74
78
392
. 96
82
162
L)
UDMH
172
24,500
. 8,230
4.010
1;410
252
22,550
3,578
•
Reference
t '
Haunjst ah , 1970
Jacobsen et al. , 1955
Haun et al. , 1970
Weeks et_aL_, 1963
Weeks Łt_aL_, 1963
Weeks et al. , 1963
Weeks et al. , 1963
Comstock et al. , 1954
• Haun et al. . 1970
Jacobsen et al. , 1955
Haun jet al. , 1970
Jacobsenjejt ah , 1955
Weeks et al. ,1963
Weeks _etaJL .1963
Haun et al. , 1970
Haun el aL , 1970
Haun_et al. ,1970
-------
Table 4
RECOMMENDED LIMITS FOR EXPOSURE
•
Compound
Hydrazine
Monomethylhydrazine
••'
1,1, Dimethylhydrazine
STPL
Time
min
10
30
60
10
30
60
10
30
60
s (25°C/760mm. Kg. )
Limit
ppm
15
10
5
9
3
I-5
50
25
15
mg/m3
20
13
7
17
6
3
127
64
38
PEL's(25°C/760mm Hg. )
Time
min
10
30
60
10
30
60
10
30
60
Limit
ppm
30
20
10
90
30
15
100
50
. 30
mg/m •*
39
26
13
169
56
28
255
127
77 . .
-42-
-------
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