EPA 560/11-80-011
APRIL 1980
CHEMICAL HAZARD INFORMATION PROFILES (CHIPs)
August 1976 - August 1978
Office of Testing and Evaluation
Office of Pesticides and Toxic Substances
Washington, DC 20460
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDES AND TOXIC SUBSTANCES
WASHINGTON, DC 20460
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Disclaimer
This document has been reviewed and approved for publication
by the Office of Testing and Evaluation, Office of Pesticides
and Toxic Substances, U.S. Environmental Protection Agency.
Approval does not signify that the contents necessarily
reflect the views and policies of the U.S. Environmental
Protection Agency, nor does mention of trade names or commercial
product constitute endorsement or recommendation for use.
11
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Foreword
Evaluations of chemical substances prepared by scientists
in EPA's Office of Testing and Evaluation, Office of Pesticides
and Toxic Substances (OPTS), to implement provisions in the
Toxic Substances Control Act (TSCA), will be published
periodically and made available to the public in the TSCA
Chemical Assessment Series. Some of the volumes in the
series are reports on single chemicals; others are compen-
diums of information received and evaluated by the Agency
about many chemicals. (The anticipated frequency of publi-
cation will vary among titles: some will be published
annually, some semiannually, and others quarterly.)
Because the chemical assessments published in this
series often will reflect initial or intermediate steps in
EPA's evaluation of a chemical under TSCA, the Agency
welcomes the submission of additional information for or
comments on its evaluations. Such submissions will be
considered either at a subsequent step in the assessment of
the subject chemical or in the decision not to proceed with
further evaluation.
All information for or comments on volumes in the TSCA
Chemical Assessment Series should be submitted to:
Director, Assessment Division (TS-792)
Office of Pesticides and Toxic Substances
U.S. Environmental Protection Agency
401 "M" Street, S.W.
Washington, D.C. 20460
111
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The TSCA Chemical Assessment Series is being distributed
through the Industry Assistance Office (IAO) in OPTS. IAO
is maintaining two mailing lists: a subscription list of
persons who want to receive all volumes in the series and a
notification list of persons who want to receive announcements
of individual volumes as they become available. Requests
for a place on either list can be made by telephoning IAO
(toll-free 800--424-9065 or, in Washington, D.C., 554-1404)
or writing to:
Industry Assistance Office (TS-799)
Office of Pesticides and Toxic Substances
U.S. Environmental Protection Agency
401 "M" Street, S.W.
Washington, D.C. 20460
Generally, five thousand copies of each volume will be
printed. When this supply has been exhausted, copies can be
purchased from the National Technical Information Service
(NTIS), whose "PB" reference number can be found in the OPTS
"Comprehensive List of Scientific and Technical Reports,"
also available from IAO.
IV
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Contents
Foreword ill
Introduction i
Acetonitrile 5
Acrolein 10
Adipate Ester Plasticizers 15
Aluminum and Aluminum Compounds 27
Aniline 39
Benzyl Chloride 43
Bromine and Bromine Compounds 48
Carbon Black 59
Cutting Fluids 72
Cyclohexylamine 78
1,6-Diaminohexane 92
1,2-Dichloroethane 96
N,N-dimethylformamide 110
Dinitrosopentamethylenetetramine 115
2,4-Dinitrotoluene 118
Ethanolamines 122
Ethylamines 126
Ethylenediamine 131
Hexachlorocyclopentadiene 135
Hexamethylphosphoramide 142
n-Hexane 147
Isopropyl Alcohol 157
Lithium and Lithium Compounds 166
Maleic Anhydride 181
Methanol 187
Methylamines 199
Morpholine 209
2-Nitropropane 212
2-Pentanone 218
Phenylenediamines 220
Phosgene 226
Sodium Azide 237
Styrene Oxide 246
Sulfur Hexafluoride 249
Tetrahydrofuran 253
2,4,6-Tribromophenol 262
Trichlorobutylene Oxide 266
1,1,2-Trichloroethane 268
Trimellitic Anhydride 273
Vinyl Bromide 277
Vinyl Fluoride 277
Vinylidene Bromide 278
Vinylidene Fluoride 279
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Introduction
This volume is a collection of forty Chemical Hazard
Information Profile (CHIP) reports on 43 chemical substances
or categories of substances prepared by the Office of Toxic
Substances* between August 1, 1976, and November 20, 1979.
Each CHIP report has been reviewed by OPTS staff, and a
tentative course of action for further consideration of the
subject chemical has been selected and documented in the CHIP
report.
Comments are sought on the accuracy and completeness of
the information contained in the CHIP reports and on the
tentative dispositions. (See the Foreword for details on
submitting comments.) All comments received will be available
for inspection and copying in the OPTS reading room, unless
specifically claimed as confidential in accordance with
applicable EPA rules and procedures (see 40 CFR Part 2 [41
FR 36902, September 1, 1976]).
Readers and commenters should be aware of the inten-
tionally limited depth of CHIP reports and of their role in
the process of chemical risk assessment conducted by OPTS.
Chemicals are chosen for CHIP preparation on the basis of
information indicating a potential for adverse health or
environmental effects, along with evidence of significant
*The Office of Toxic Substances (OTS) became the Office of
Pesticides and Toxic Substances (OPTS) on October 19,
1979.
Room E447 at EPA Headquarters, 401 M Street, S.W., Washington,
D.C. 20460.
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commercial production or environmental exposure. Such
information may come from a variety of sources, including
official submissions to EPA, scientific articles in the open
literature, government reports, scientific papers presented
at meetings, and recommendations from the public.
The CHIP itself is a brief summary of readily available
information concerning the health and environmental effects
and exposure potential of a chemical. Information gathering
for a CHIP is generally limited to a search of secondary
literature sources such as computerized data bases, abstracts,
government reports, scientific review documents, and reference
works. The literature search for a CHIP is not intended to
be exhaustive; however, in-depth searches on specific topics
may be done on a case-by-case basis. Relevant literature is
usually reported in the form of a narrative summary. Key
experimental conditions and results are briefly described
for relevant studies. The information in a CHIP is reported
as it appears in the published literature; in general, no
attempt is made to independently evaluate or validate published
data at this stage of assessment. An effort has been made
in preparing this volume to have each CHIP conform to a
consistent format; however, because these CHIPS were prepared
during a three-year period by a variety of authors, a few
of the reports do deviate from the format selected.
The OPTS chemical risk assessment process is a sequential
one in which chemical problems are evaluated in greater
detail at each succeeding stage of the process. In its
early stages, Limited amounts of information are evaluated
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on a relatively large number of chemicals; in later stages,
more comprehensive information on a relatively few chemicals
is assessed. At every stage, the decision is made to evaluate
a chemical further or allow it to exit from the process.
The decisions that can be made at any given stage are limited
by the scope and depth of the data gathering and analysis
completed at that stage. Thus, decisions made at the early
stages of assessment tend to be more general and tentative
than those made at the later stages.
Preparation of a CHIP is part of the first stage in
this overall assessment process. The CHIP is OPTS's initial
attempt to collect and organize into a report a broad range
of information on a chemical of concern. The purpose of a
CHIP is to enable OPTS to decide tentatively on an appropriate
course of action for the subject chemical. Determination of
the need for specific regulatory action is not the immediate
goal of the CHIP; rather, it is intended to identify and
characterize problems that subsequently may require more
thorough investigation and evaluation.
A broad range of possibilities exists regarding the
steps taken following the CHIP. Some common alternatives
for follow-up action include (1) consideration for more
detailed assessment within OPTS; (2) consideration for a
testing rule under section 4 of TSCA; (3) acquisition of
more information via section 8 of TSCA; (4) referral to
other EPA offices or other Government agencies for further
consideration and follow-up, as appropriate; and (5) assignment
of "low priority" for further assessment by OPTS.
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CHEMICAL HAZARD INFORMATION PROFILE
Acetonitrile
Date of report: March 9, 1978
This chemical was chosen for study because of its
structural similarity to acrylonitrile, a suspected car-
cinogen.
The following recommendations are made regarding
further OTE evaluation of the possible health or environ-
mental hazards of acetonitrile:
*
(1) Obtain better information on potential for envi-
ronmental release and human exposure. Available
information indicates that significant quantities
of acetonitrile may be released to the environ-
ment. Use of TSCA Section 8(a) authorities and
EPA monitoring of potential release sources should
be considered to obtain such information.
(2) Require TSCA Section 8(d) submissions. Informa-
tion on carcinogenicity arid teratogenicity is
quite sketchy. Reported teratogenicity studies
indicate equivocal results.
(3) Refer acetonitrile to EPA-ORD for mutagenicity
testing. No mutagenicity data are currently
available.
(4) Update this Chemical Hazard Information Profile
(CHIP) based on the additional data found.*
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
*Subsequent to the review of this CHIP and the selection of
the tentative dispositions given above, the TSCA Inter-
agency Testing Committee recommended acetonitrile for
primary consideration for possible testing under Section
4(a) of TSCA (44 FR 31866 [June 1, 1979]).
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Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
4-V\£i e* 11 V\ -i £* /-• 4- i-*ViomT r»aT
the subject chemical.
Chemical Identity
Acetonitrile (CH_-C=N) is a colorless liquid with an
aromatic odor. Its boiling point is 81°C, and its melting
point is -41.9°C. Acetonitrile1s density is 0.7868 (at
20°C), and its vapor pressure is 100 mm Hg (at 27°C). It
has a high polarity, which may contribute to its strong
reactivity. Acetonitrile is freely miscible with water,
alcohol, ethyl acetate, acetone, ether,*chloroform, carbon
tetrachloride, and ethylene chloride (ITII, 1976). It is
explosive at concentrations of 4.4 to 16.0% by volume in
air. Acetonitrile is considered a dangerous disaster hazard
since it emits toxic cyanide fumes when heated to decomposi-
tion (120°C with alkali). It will react with water, steam,
or acids to produce toxic and flammable vapors arid can react
vigorously with oxidizing materials (Sax, 1968). Synonyms
for acetonitrile include methyl cyanide, cyanomethane, and
ethanenitrile.
Production and Use
Acetonitrile can be manufactured by the vapor-phase
ammonolysis of glacial acetic acid. The acetonitrile yield
is 85-95% after dehydration of the reaction products (Ing-
walson, 1971). Another source of acetonitrile is as a by-
product of the propylene-ammonia process for the manufacture
of acrylonitrile (Hawley, 1977).
There are only two domestic producers of acetonitrile:
E. I. du Pont de Nemours and Co., Inc. (Elastomer Chemicals
Department, Beaumont, Tex.) and Standard Oil Co. of Ohio
(Vistron Corp., a subsidiary, Chemicals Department, Lima,
Ohio) (SRI, 1975). Annual production has been estimated to
be 135 x 106"lb (Dorigan et al., 1976).
Acetonitrile is used as a solvent in hydrocarbon extrac-
tion processes (especially for butadiene) and as a specialty
solvent.*" Acetonitrile is the starting material for aceto-
phenone and naphthalene-acetic acid, thiamine, and acetamine.
*Acetonitrile may be used as a specialty solvent to dissolve
cationic textile dyes (Textile World, 1979), to recrystallize
steroids, and to remove tars, phenols, and coloring matters
from petroleum hydrocarbons (Stecher, 1969).
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It is a chemical intermediate in the manufacture of vitamin
B,, substituted pyrimidines, and Pharmaceuticals. Aceto-
nitrile is used as a solvent in the separation of fatty
acids from vegetable oils (Hawley, 1977).
Health Aspects
The TLV for acetonitrile is 40 ppm (ACGIH, 1971). This
is also the time weighted average for worker exposure.
Acetonitrile is easily absorbed through mucous membranes
because of its high solubility in water. The oral LD
for rats is 3,800 mg/kg. Four-hour rat inhalation studies
give an LCsg of 8,000 ppm. The LDgp for intraperitoneal
injections of acetonitrile in mice is 500 mg/kg. LDsn
for standard application of acetonitrile to rabbit skin is
1,250 mg/kg. The 96-hr aquatic toxicity rating is 1,000 ppm
(NIOSH, 1976).
The toxic action of acetonitrile is the same in most
animals as it is in man. The compound is metabolized to
hydrocyanic acid, which can be found in high levels in the
brain, heart, kidney, and spleen (Haguenoer, 1975). Acute
symptoms of acetonitrile inhalation include headache, dizzi-
ness, increased respiration rate, rapid pulse, vomiting,
unconsciousness, and convulsions (coma and death). Chronic
symptoms of acetonitrile inhalation include headache,
anorexia, dizziness, weakness, and dermatitis (ITII, 1976).
Other chronic effects may include growth retardation,
metabolic disturbances, and liver enlargement (Dorigan et
al., 1976).
Acetonitrile is easily absorbed through mucous mem-
branes because of its high solubility in water. Human
inhalation studies on acetonitrile have been conducted.
Three subjects were exposed to 40 ppm for 4 hr and two
subjects were exposed to 80 and 160 ppm for 4 hr. No
adverse reactions were reported at the 40 ppm and 80 ppm
inhalation levels. At 160 ppm, one subject noted a slight
flushing of the face 2 hr after inhalation and a slight
feeling of bronchial tightness 5 hr later. There was no
detectable blood cyanide at 40 or 80 ppm. At 160 ppm, there
were insignificant changes in blood cyanides. At 40 ppm,
one subject exhibited a slightly elevated urinary thiocya-
nate level. The urinary thiocyanate level changes were
insignificant at 40 ppm; they were inconsistent at 80 ppm
and not significant at 160 ppm (Pozzani, 1959).
Inhalation of high concentrations of acetonitrile
vapors can be fatal. Symptoms are usually delayed 4 to 16
hr and begin with stomach pains and vomiting. Headache,
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chest pain, asthenia, hypotension, generalized pain, and
weakness may follow. The victim may then lapse into coma
and convulsions. Death is preceded by a failing of the
central nervous system (Desquidt, 1974).
The toxic action of acetonitrile is due to the in vivo
metabolism to hydrocyanic acid. Autopsy of one victim
revealed densification of the inferior lobes of the lungs
and total diffuse necrosis of the brain (Desquidt, 1974).
Liquid acetronitrile may also cause skin irritation by
direct contact (Stecher, 1969). No references to the muta-
genicity of acetonitrile have been found. The reported
teratogenic effects of acetonitrile are conflicting. Fetal
malformations have been reported in rats from intraperi-
toneal doses from 0.2 to 1.0 ml/kg (Dorigan et al., 1976).
However, other investigators have been unable to produce
malformations in fetal pigs (Crowe, 1973). Attempts to
produce teratogenic effects in rodents have produced incon-
sistent results.
Environmental Aspects
10
6 -
Based on an estimated annual production of 135 x
Ib of acetonitrile, 69.5 x 10 Ib is released to the envi-
ronment annually (Dorigan et al., 1976). It is unclear
whether this release rate accounts for acetonitrile waste
from acrylonitrile production. This process may produce and
release over 20 x 10 Ib per year (Gruber, 1976). In the
atmosphere acetonitrile is highly reactive to oxidizing
materials. It is infinitely soluble in water (Dorigan et
al., 1976) and has been found to be relatively stable in
water.* The BOD of 1 mg acetonitrile has been estimated to
be 1.4 mg.
*A concentration of approximately 2.4 mg/1 can be maintained in
reservoir water for 4 days (Rubinskii, 1969).
REFERENCES
ACGIH (American Conference of Governmental Industrial
Hygienists). Documentation of TLV's. Cincinnati, Ohio.
1971.
Crowe, M. W. Teratogenic capability of tobacco (Nicotiana
tobacum) and those chemicals commonly applied to the growing
plant. Tob. Health Workshop Conf. Proc. 4JI:98-202, 1973.
Desquidt, J. et al. Poisonings by acetonitrile. A fatal
case. Eur. J. Toxicol. 7(2):91-97, 1974.
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Dorigan, J. et al. Scoring of Organic Air Pollutants.
MITRE Corp. (for EPA). 1976.
Gruber, G. I. Assessment of Industrial Hazardous Waste
Practices, Organic Chemicals, Pesticides and Explosives
Industries. Redondo Beach, Calif., TRW (for EPA). 1976.
Haguenoer, J. M. et al. Experimental acetonitrile intoxica-
tion: Acute intoxication by an intraperitoneal route. Eur.
J. Toxicol. 8_(2) :94-101, 1975.
Hawley, G. G. (ed.). Condensed Chemical Dictionary, 9th ed.
New York, Van Nostrand Reinhold Co. 1977.
Ingwalson, R. W. Nitriles. Iri Kirk-Othmer Encyclopedia of
Chemical Technology, Supplement. 1971.
ITII (International Technical Information Institute). Toxic
and Hazardous Industrial Chemicals Safety Manual. Tokyo.
1976.
NTOSH. Registry of Toxic: Effects of Chemical Substances,
1976 ed.
Pozzani, U. C. et al. An investigation of the mammalian
toxicity of acetonitrile. J. Occup. Med. 1^634, 1959.
Rubinskii, N. D. Effect of acetonitrile and succinonitrile
on the sanitary conditions of reservoirs. Gig. Naselennykj
Mest 8:20-24, 1969. (From Chem. Abstr. JH:91026J)
Sax, N. I. Dangerous Properties of Industrial Materials, 3rd
ed. New York, Van Nostrand Reinhold Co. 1968.
SRI (Stanford Research Institute). Directory of Chemical
Producers. Menlo Park, Calif. 1975.
Stecher, P. G. (ed.). The Merck Index. Rahway, N.J., Merck
and Co., Inc. 1969.
ADDENDUM
It has been found that a standardized (Crowe, 1976) second
puff of cigarette smoke contains 0.31 mg acetonitrile. A smoker
may adsorb between 73 and 82% of this, depending on past smok-
ing habits.
Reference
Dalman, T. et al. Mouth adsorption of various compounds in
cigarette smoke. Arch. Environ. Health 16(6): 831-835, 1968.
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CHEMICAL HAZARD INFORMATION PROFILE
Acrolein
Date of report: March 10, 1978
This chemical was chosen for study because of its
reported presence in air and water samples.
Acrolein is not recommended for further priority evalu-
ation within OTS at this time. Available information indi-
cates that most human exposure to acrolein is confined to
the workplace. There is an existing OSHA standard for
acrolein. Significant environmental exposure is unlikely
because of acrolein's high reactivity and apparently low
release rate.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report eire tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Acrolein (2-propenal, acrylaldehyde, or allyl aldehyde)
is a colorless to yellowish liquid. It has a highly dis-
agreeable, choking odor and is flammable. Acrolein is
soluble in water, alcohol, and ether. It has a boiling
point of 52.7°C. Upon exposure to light and air, acrolein
polymerizes to form disacryl, an inactive, gelatinous sub-
stance (Hawley, 1971).
Production and Use
Acrolein is currently produced only by Shell Chemical
Co., Norco, La., and Union Carbide Corp., Chemicals and
Plastics Division, Taft, La. (SRI, 1977) . The only method
used to manufacture acrolein is the catalytic vapor-phase
oxidation of propylene (School, 1973). U.S. production of
isolated acrolein in 1974 is estimated to have been 61
million Ib. An additional 100-150 million Ib was produced
and consumed captively for production of acrylic acid and
esters (U.S. EPA, 1977b).
The U.S. consumption pattern of isolated acrolein in
1974 was estimated as follows: glycerin, 50%; synthetic
10
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methionine, 25%; other applications, 25%. "Other applica-
tions" include: manufacture of 1,2,6-hexanetriol, glutaral-
dehyde, glyceraldehyde, perfume, colloidal forms of metals,
and numerous other organic compounds; as an aquatic herbi-
cide, molluscicide, slimicide, and algicide; and in etheri-
fication of food starch (U.S. EPA, 1977b).
Health Aspects
General Toxicity
Acrolein is a severe irritant to the eyes and respira-
tory tract. Yant et al. (1930) reported that 1 ppm caused
"practically intolerable eye irritation with lacrimation"
within 5 min of exposure. The rat inhalational LCsg is
0.75 mg/1 for 10-min exposure (Champeix and Catilina, 1975).
Rat oral LDcn is 46 mg/kg, and human LC_n is 153 ppm/10 min
(NIOSH, 1975).
Rats continuously exposed to 0.55 ppm acrolein for 11
to 21 days had significantly lower body weight, liver
weight, and serum acid phosphatase levels than controls.
They also showed signs of upper respiratory tract irrita-
tion, significant lowering of alveolar macrophage number,
and high susceptibility to Salmonella enteritidis infection
(Bouley et al., 1976).
Continuous 90-day exposure at 0.22 ppm caused inflamma-
tion in liver, lung, kidney, and heart of monkeys, guinea
pigs, and dogs. Exposure to 1.8 ppm caused squamous cell
metaplasia and basal cell hyperplasia of the trachea in
monkeys (Lyon et al., 1970).
Carcinogenicity
In a study with hamsters, Peron and Kruysse (1971)
found no tumors attributable to acrolein exposure (4.0 ppm,
7 hr/day, 5 days/week, 52 weeks). Acrolein exposure did not
increase the number of tumors in animals treated with both
acrolein and either benzo(a)pyrene or diethylnitrosamine.
Mutagenicity
Acrolein has been found to be mutagenic in the yeast
S. cerevisiae (Izard, 1973), the alga D. bioculata (Izard,
1967), and the fruit fly D. melanogaster (Rapoport, 1948).
Negative results have been found in the bacteria
E. coli (Ellenberger and Mohn, 1976) and S. typhimurium
(Anderson et al., 1972) and in the mouse dominant lethal
test (Epstein et al., 1972).
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Hygienic Standards
U.S. Occupational Health Standard - air: TWA, 0.1 ppm.
American Conference of Government Industrial Hygienists:
TLV, 0.1 ppm.
Environmental Aspects
The total release rate of acrolein into the environment
is not known. Besides fugitive emissions from industrial
processes, acrolein is formed in the environment by burning
tobacco and by heating fats or glycerine (Plotnikova, 1957).
In water, oxidation of acrolein by RO radical may be
fairly rapid (U.S. EPA, 1977a). Biodegradation in water
also appears rapid, as the 10-day BOD is 33% of the theo-
retical value (Dorigan et al., 1976). In air, aldehydes are
expected to photodi.ssociate to RCO and H atoms rapidly and
competitively with their oxidation by HO radical, for a
half-life of 2 to 2; hr (Calvert and Pitts, 1966; Hendry,
1977) .
The 24-hr and 48-hr LC5Q values to harlequin fish are,
respectively, 0.14 and 0.06 ppm (Alabaster, 1969). Exposure
to 1.0 ppm totally inhibited multiplication of the marine
alga D. bioculata (Champeix and Catalina, 1975) . Acrolein
has demonstrated ciliastatic effects in mammals (Guillerm et
al., 1961), molluscs (Wynder et al., 1965), and algae (Izard
and Testa, 1968) .
REFERENCES
Alabaster, J. S. Survival of fish in 164 herbicides, insec-
ticides, fungicides, wetting agents and miscellaneous sub-
stances. Int. Pest. Contr. 1JL (2) : 29-35, 1969.
Anderson, K. J. , E., G. Leighty, and M. T. Takahashi. Evalu-
ation of herbicides for possible mutagenic properties. J.
Agr. Food Chem. 2_0 (3) : 649-656 , 1972.
Bouley, G. , A. Dub]:euil, J. Godin, M. Boisset, and C. Boudene.
Phenomena of adaptation in rats continuously exposed to low
concentrations of acrolein. Ann. Occup. Hyg. 19(l):27-32,
1976.
Calvert, J. G., and J. N. Pitts. Photochemistry. New York,
John Wiley and Sons. 1966. (As cited by U.S. EPA, 1977a)
12
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Champeix, J., and P. Catilina. Les Intoxications par 1'Acro-
leine. Masson, Paris, 1975. (As cited by Izard and Liber-
mann, Mutat. Res. 4_7_:133, 1978)
Dorigan, J., B. Fuller, and R. Duffy. Scoring of Organic
Air Pollutants. Chemistry, Production and Toxicity of
Selected Synthetic Organic Chemicals. MITRE Corp. 1976.*
Ellenberger, J., and G. R. Mohn. Comparative mutagenicity
of cyclophosphamide and some of its metabolites. Mutat.
Res. 3B_: 120-121, 1976. (As cited by Izard and Libermann,
Mutat. Res. £7:125, 1976)
Epstein, S. S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop.
Detection of chemical mutagens by the dominant lethal assay
in the mouse. Toxicol. Appl. Pharmacol. £3:288-325, 1972.
(As cited by Izard and Libermann, Mutat. Res. 4_7_:132, 1978)
Guillerm, R., R. Dadre, and B. Vignon. Effects inhibiteurs
de la fumee de tabac sur 1'activite ciliavie de I1 epithe-
lium respirative, et natures des composants responsables.
C. R. Acad. Nat. Med. 14^5:416-425, 1961. (As cited by Izard
and Libermann, Mutat. Res. 4J7:123, 1978)
Hawley, G. G. (ed.). The Condensed Chemical Dictionary, 8th
ed. New York, Van Nostrand Reinhold Co. 1971.
Hendry, D. G. Private communication, 1977. (As cited by
U.S. EPA, 1977a)
Izard, C. Sur la multiplication de Dunaliella bioculata en
presence de la phase gayeuse de fumee de cigarette et sur
1'obtention de mutations en presence d1 acroleine. C. R.
Acad. Sci. Ser. D 265:1799-1802, 1967. (As cited by Izard
and Libermann, Mutat. Res. 4_7:128, 1978)
Izard, C. Recherches sur les effects mutagenes de 1' acro-
lein et de ses deux epoxydes: le glycidol et le glycidal,
sur Saccharomyces cerevisiae. C.R. Acad. Sci. Ser. D 276;
3037-3040, 1973. (As cited by Izard and Libermann, Mutat.
Res. 47:126, 1978)
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some infor-
mation is not possible. The environmental release data were
taken from the NSF/Rann Research Program on Hazard Priority
Ranking of Manufactured Chemicals.
13
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Izard, C., and P. Testa. Recherches sur les effects de
la fumee de la cigarette et de certains constituants sur la
motilitie et la multiplication du Dunaliella bioculata.
Ann. Dir. Equip. Exploit. Ind. Tab. Alumettes, Sec. 1, No.
6, p. 121-156, 1968. (As cited by Izard and Libermann,
Mutat. Res. 4_7_:124, 1978)
Lyon, J. P., T. J. Jenkins, Jr., R. A. Jones, R. A. Coon,
and J. Siegel. Repeated and continuous exposure of labora-
tory animals to acrolein. Toxicol. Appl. Pharmacol. IT_(3) :
726-732, 1970.
NIOSH. Registry of Toxic Effects of Chemical Substances.
1975.
Peron, V. J., and A. Kruysse. Effects of exposure to acro-
lein vapor in hamsters simultaneously treated with benzo(a)-
pyrene or diethylnitrosamine. J. Toxicol. Environ. Health
3_:379-394, 1971.
Plotnikova, M. M. Acrolein as an atmospheric air pollutant.
Gig. Sanit. ^2 (6):1015, 1957. From B. S. Levine (ed.),
U.S.S.R. Literature on Air Pollution and Related Occupa-
tional Diseases, vol. 3, 1960, p. 188-194.
Rapoport, I. A. Mutatsii pod vlianiem mepredel1 nyh al'
degidov. Dokl. Akad. Nauk SSSR 61:713-715, 1948. (As cited
by Izard and Libermann, Mutat. Res. £7:131, 1978)
SRI (Stanford Research Institute). Directory of Chemical
Producers. Menlo Park, Calif. 1977.
School, G. E. Make acrolein from propylene. Hydrocarbon
Process., Sept. 1973, p. 218-220.
U.S. EPA. Review of the Environmental Fate of Selected
Chemicals Task 3. EPA 560/5-77-003, PB 267121/AS. 1977a.
p. 52.
U.S. EPA. A Study of Industrial Data on Candidate Chemicals
for Testing. EPA 560/5-77-006. 1977b. p. 487, 488.
Wynder, E. L., D. A. Goodman, and D. Hoffman. Ciliatoxic
components in cigarette smoke, II. Carboxylic acids and
aldehydes. Cancer 1^:505-509, 1965. (As cited by Izard and
Libermann, Mutat. Res. 4^:123, 1978)
Yant, W. B., H. Schrenk, P. Patty, and R. Sayers. Acrolein
as a warning agent for detecting leakage of methyl chloride
from refrigerators. U.S. Bureau of Mines Report of Inves-
tigation No. 3027. (As cited by Kane and Alarie, Sensory
irritation to formaldehyde and acrolein during single and
repeated exposures in mice, American Ind. Hyg. Assoc. J.,
vol. 38, 1971) 14
-------
CHEMICAL HAZARD INFORMATION PROFILE
Adipate Ester Plasticizers
Date of report: January 5, 1978
This category of chemicals was chosen for study after
incidents of respiratory ailments ("meat-wrappers syndrome")
were reported in workers exposed to food wraps which contain
adipate ester plasticizers. Although no information sup-
porting these claims was found in the course of preparing
this document, information was found which indicates a
potential for mutagenic and teratogenic effects.
Phase I assessment is recommended for the adipates.
Relatively little information was found concerning either
the amount of adipate esters released into the environment
or the environmental fate of these chemicals. This lack of
information, coupled with the fact that adipate esters are
produced in fairly high volume, suggests that environmental
monitoring may be needed to allow better estimation of the
extent of nonoccupational exposure to adipate esters.
Monitoring data obtained by SAD will be forwarded to CREB
for use in the Phase I assessment.
It is also recommended that CHIB perform a chemical
technology review of diacid plasticizers.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Adipate ester plasticizers are nonvolatile oily liquids
or low-melting solids. They are generally used to improve
the low-temperature flexibility of polyvinyl chloride (PVC)
compounds (CCD, 1977).
A plasticizer is an organic compound added to a high-
molecular-weight polymer both to facilitate processing and
to increase the flexibility and toughness of the final
product by internal modifications (solvation) of the polymer
molecule. The polymeric structure is initially held together
15
-------
by secondary valence bonds; the plasticizer replaces some of
these with plasticizer-to-polymer bonds, thus aiding move-
ment of the polymer chain sections. Plasticizers are
classified as primary (high compatibility) and secondary
(limited compatibility).
The most widely used adipate ester plasticizer is di(2-
ethylhexyl) adipate, which accounts for about two-thirds of
the adipate ester plasticizer market. The other large-
volume component of this market is n-octyl n-decyl adipate,
representing approximately 13% of the total. The balance is
divided among a number of adipic acid esters including
diisodecyl adipate, diisooctyl adipate, n-hexyl n-decyl
adipate, di(2-butoxyethoxy)ethyl adipate, and others (CEH,
1976).
0 = C - CH0 - CH, - CH0 - CH, - C = 0
^ £t £• £»
OR OR
General formula for adipic acid esters
Production and Use
Most plasticizers are products of simple esterification
reactions, which can be readily carried out in heated
kettles with agitation and provisions for water take-off.
Nevertheless, while some plants produce plasticizers by such
batch methods, other, newer plants operate continuously and
in a highly automated fashion. Esterification catalysts
such as sulfuric acid or p-toluenesulfonic acid speed the
reaction and are later removed in a washing step. The
purity requirements for commercial plasticizers are very
high; adipate esters are usually almost colorless and have
little odor (CEH, 1976).
Adipic acid esters are prepared via the reaction of
adipic anhydride with an aliphatic alcohol to yield the
desired product (CEH, 1976).
The production of adipate esters has increased appre-
ciably in recent years. The major producers of adipate
plasticizers are Hatco, Monsanto, Rohm and Haas, Tennessee
Eastman, and U.S.S. Chemicals. Only Monsanto is a major
producer of adipic acid and is also believed to be the
largest producer of the most popular adipate plasticizer,
di(2-ethylhexyl) adipate. See Table 1 for annual domestic
production figures. Table 2 presents the 1971 production
figures for the major adipate plasticizers. Along with the
major adipate plasticizers are a number of apparently
small-volume adipate plasticizers used in specialty applica-
tions. Table 3 lists all the adipate plasticizers identi-
fied in the Modern Plastics Encyclopedia (1975). Despite
16
-------
the significant production volume of the adipate plasti-
cizers, as a class they represent only a small fraction of
the total plasticizer market. As can be seen in Table 4,
adipates represent less than 5% of a market dominated by
phthalate esters.
Table 1. Annual Domestic Production of Adipate Plasticizers
(millions of Ibs)
Di(2-ethylhexyl)
Year adipate Others Total
1955
1960
1965
1970
1974
2.7
3.0
14.7
35.0
40.6
7.9
14.3
33.1
19.0
23.5
10.6
17.3
47.8
54.0
64.1
Source: CEH, 1976.
Includes primarily n-octyl n-decyl adipate and the follow-
ing: diisodecyl adipate; diisooctyl adipate; n-hexyl n-
"decyl adipate; and di(2-butoxyethoxy)ethyl adipate.
Table 2. Adipate Ester Production, 1971
Type %^
Di(2-ethylhexyl) adipate (DOA) 55
Dioctyl adipate 14
n-Octyl n-decyl adipate 13
Diisodecyl adipate 6
n-Hexyl n-decyl adipate 5
Di(2-butoxyethoxy)ethyl
adipate 3
Source:CEH, 1976.
17
-------
Table 3. Commercial Adipate Ester Plasticizers
Name No. of manufacturers and importers
Dimethyl adipate 7
Dibutyl adipate 2
Diisobutyl adipate 3
Di(2-ethylhexyl) adipate (DOA) 16
Dinonyl adipate 2
n-Octyl n-decyl adipate 4
Diisodecyl adipate 9
Polypropylene adipate 1
Source:U.S. EPA (1979).*
This production range information does not include any
production/importation data claimed as confidential by the
person(s) reporting for the TSCA Inventory, nor does it include
any information which would compromise Confidential Business
Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the
limitations contained in the Inventory Reporting Regulations
(40 CFR 710).
Table 4. U.S. Production and Plasticizers by Major Type, 1974
Type %_
Phthalate esters 71.8
Epoxy esters 8.8
Phosphate esters .3
Adipate esters 3.8
Polymeric plasticizers 3.0
Other aliphatic esters 1.1
Other plasticizers 4.2
Source:CEH, 1976T
Over 85% of all aliphatic adipate ester plasticizers
are used to impart low-temperature flexibility to polyvinyl
chloride (PVC) formulations (see Table 5). Adipates repre-
sent the predominant category of aliphatic plasticizers;
azelates and sebacates are small-volume speciality aliphatic
plasticizers. In recent years, with the increased avail-
ability of cheaper linear phthalates, the total consumption
of aliphatic plasticizers has remained virtually static.
In addition to PVC applications, adipate plasticizers
are used to a much lesser extent with natural and synthetic
rubbers, polystyrene, and cellulose derivatives (e.g.,
nitrocellulose lacquers). These plasticizers are character-
ized by low initial viscosity stability for plastisol
18
-------
Table 5. Domestic Aliphatic Plasticizera Consumption, 1974 (%)
Application Consumption
Use with polymers
PVC resins 76
Other vinyl resins
Cellulose ester plastics 3
Synthetic elastomers
Other polymers
Other uses 21
Total 100
Source: CEH, 1976.
^Includes
azelates.
alncludes adipates (predominantly), sebacates, and
formulations, excellent clarity for sheeting and film, good
electrical resistivity, and low volatility for high-tempera-
ture applications such as wire covering and insulation.
In PVC plasticizers, adipate diesters [chiefly di(2-
ethylhexyl) adipate] are used to impart low-temperature
flexibility and resilience when, and to the extent, needed.
Examples of PVC plastics containing discrete amounts of
adipate plasticizers include coated fabrics for automobile
seating, film for produce and meat packaging, insulation of
certain types of electrical and communication wires, and
others. Adipate plasticizers were among the first plasti-
cizers approved by FDA for use in food storage and prepara-
tion areas, where they have found increasing popularity
(e.g., coating for refrigerator shelves and kitchen appli-
ances) . The major application of adipate plasticizers in
this field is in food wraps and packaging, and this market
is expanding rapidly (CEH, 1976).
One of the chief concerns involved in the selection of
the correct adipate plasticizer is the compatibility each
has for the particular resin. Adipic acid esters of linear
alcohols, chiefly in the n-octyl to n-decyl range, for
example, have found increasing use because their effective-
ness in imparting low-temperature flexibility is somewhat
greater than that of esters of branched alcohols; in addi-
tion, they are also much less volatile. On the other hand,
their compatibility and fusion characteristics are inferior
19
-------
to those of di(2-ethylhexyl) adipate (CEH, 1976). Refer to
Table 6 for a summary of compatibility qualities of several
adipate plasticizers.
Table 6. Adipate Plasticizer Compatibility with Various Plastics'
Plasticizer
CA CAB CN EC PM PS VA VB PVC
Diisobutyl adipate
DOA
Diisodecyl adipate
Di (2-butoxye'thyl)
adipate
U
P
P
P
C
C
C
C
C
C
C
C
U
C
C
C
U
P
P
C
U
C
P
C
C
P
P
P
U
P
P
C
C
C
C
C
Source: Adapted from: Darby and Sears, 1968.
aResins used: CA, cellulose acetate; CAB, cellulose acetate-
butyrate; CN, cellulose nitrate; EC, ethylcellulose; PM,
polymethyl methacrylate; PS, polystyrene; VA, polyvinyl
acetate; VB, polyvinyl butyryl; PVC, polyvinyl chloride.
Code for compatibility: C, compatible; P, partially com-
patible; U,. unknown.
Health Aspe_cts
Dominant Lethal Mutations and Antifertility Effects
Male mice of demonstrated fertility were injected IP with a
single dose of 0.5, 1.0, 5.0, or 10.0 ml/kg of di(2-ethylhexyl)
adipate (DOA) or a single injection of 0.44, 0.73, 1.10, or
1.46 ml/kg of diethyl adipate (DEA). Ten males were injected
at each dose level and allowed to mate with two virgin
females per week for 8 weeks. Both DOA and DEA produced
dose-related anti-fertility and mutagenic effects, as indicated
by a reduced percentage of pregnancies and an increased
number of early fetal deaths. The highest dose of DOA and
the two largest doses of DEA yielded a distinct reduction in
the incidence of pregnancies, especially during the first 3-
to 4-week period postinjection. This antifertility effect
was less evident with the lower dose levels. There also
occurred a reduction in the number of implantations and live
fetuses per pregnancy for one or more of the higher dose
levels of both DOA and DEA. Mutagenic effects, as expressed
by an increase in the number of early fetal deaths, dis-
played a significant degree of dose dependence, with the
higher doses yielding more early fetal deaths than the lower
doses. These dominant lethal mutations were observed for
20
-------
both adipates during the 3-week period immediately following
injection. However, DOA also induced dominant lethal effects
during the period 4-8 weeks postinjection. This indicates
that DOA produced dominant lethal mutations in both the
postmeiotic and premeiotic stages of spermatogenesis in mice
(Singh et al., 1975).
Embryotoxic and Teratogenic Effects
Seven adipates were evaluated for their embryonic-fetal
toxicity and teratogenic effects in rats. The tested adi-
pates included dimethyl, diethyl (DBA), dipropyl, diisobutyl,
di-n-butyl, di(2-ethylhexyl) (DOA), and dicyclohexyl adipate.
The adipates were tested in female rats by the IP injection
of varying doses on the 5th, 10th, and 12th days of gestation
(see Table 7).
Table 7. Embryonic-Fetal Toxicity of Adipate Esters on Rat Fetuses
Abnormalities
Injection vol
Adipate ester (ml/kg) Resorptions (%) Gross Skeletal Visceral
Dimethyl
Diethyl
(DEA)
Dipropyl
Diisobutyl
Di-n-butyl
Di (2-ethylhexyl)
(DOA)
Dicyclohexyl
0.0603
0.1809
0.3617
0.6028
0.0837
0.2512
0. 5024
0.8373
0.1262
0.3786
0.7572
1.2619
0.1983
0.5950
1. 1900
1.9833
0.1748
0.5244
1.0488
1.7480
1.00
5.00
10.00
0.1700
0.5100
1.0201
1. 7002
6.8
14.1
1.8
5.7
1.9
7.0
9.3
10.7
3.2
10.9
9.8
20.0
3.6
1.6
4.8
3.2
3.8
4.9
2.9
9.4
5.3
3.1
7.0
14.5
19.6
19.4
20.0
0
1.8
3.6
8.0
0
1.9
2.0
4.2
0
2.0
3.6
5.6
0
3.2
1.7
8.3
0
1.7
3.0
5.4
0
1.6
3.8
0
10.0
6.3
8.5
0
7.4
13.8
19.2
0
0
4.0
8.0
0
0
0
5.3
0
6.3
10.0
9.7
0
0
0
6.7
3.6
3.4
7.1
0
0
3.8
4.0
0
0
0
0
8.3
0
4.0
0
0
0
0
0
0
0
0
3.4
0
3.7
0
3.8
0
3.2
4.0
0
0 ,
0
0
Source:Adapted from Singh et al., 1973.
21
-------
The administered doses were based on the acute toxicity of
each compound as follows: 1/30, 1/10, 1/5, and 1/3 of the
acute LDso for each substance (except DOA, which had little
apparent acute toxicity). The rats were sacrificed on the
20th day of gestation (1 day before expected parturition)
and examined for gross, skeletal, and visceral abnormalities.
All of the adipates were found to exert some degree of
damage upon the developing embryo and fetus:
(1) Dicyclohexyl adipate caused a significant increase
in resorptions at all four dose levels, indicating
an early embryotoxic effect. In addition, dead
fetuses were found at all dose levels, indicative
of a later toxic action as well. A number of
gross abnormalities were noted at the three higher
doses; most abnormalities took the form of heman-
giomas of various parts of the body, although
twisted hindlegs were often also observed. Skel-
etal abnormalities were seen in a few mice at the
two highest dose levels, while no visceral changes
were seen in any of the groups.
(2) Dimethyl adipate also displayed a considerable
degree of embryotoxicity and teratogenicity. In
the highest dose group, several fetuses had heman-
giomas, 5 of 26 examined fetuses had skeletal
abnormalities, 1 fetus lacked a left kidney, and 1
had an angulated anal opening. In the second
highest dose group, 1 fetus did not have a tail and
4 of 29 examined had skeletal abnormalities. The
next lower dose level produced several abnormal
fetuses, albeit at a lower frequency, with changes
similar to those seen at the two higher levels.
The lowest dosage did not produce any noted
abnormalities.
(3) Diisobutyl adipate produced a number of abnormal
changes in the offspring of treated rats. At the
highest level, hemangiomas were noted in several
fetuses, as were twisted"hindlegs and other
skeletal malformations. The next lower dose
groups yielded fetuses with hemangiomas and skel-
etal malformations but no examples of twisted
hindlegs. No abnormalities were seen in the
lowest group.
(4) Diethyl, dipropyl, di-n-butyl, and di(2-ethylhexyl)
adipate produced few gross, skeletal, or visceral
abnormalities; these occurred predominantly at the
higher dose levels.
22
-------
The study concluded that, while all of the tested adi-
pates exerted some deleterious effects on the developing
embryo and fetus, the degree of injury was significantly
less than that seen with similar doses of phthalate ester
analogs (Singh et al., 1973).
Acute Toxicity
The adipate esters are characterized by a low to moder-
ate degree of acute toxicity. Table 8 presents a summary of
the results from several acute toxicity studies.
Table 8. Summary of Adipate Ester Acute Toxicity Studies
Adipate ester
Dimethyl
Diethyl
Dipropyl
Di-n-butyl
Diisobutyl
Dicyclohexyl
Di(2-ethylbutyl)
Di(2-ethylhexyl)
(DO A)
Di (2-hexyloxyethyl)
Di[2-(2-ethylbutoxy) ] ethyl
Didecyl
aSingh et al. , 1973.
°Fassett, 1963.
, Singh et al., 1975.
Smyth et al. , 1951.
eSmyth et al. , 1954.
Oral LDso
(g/kg)
h
1.6D
A
12. 9d
5 6e
9.'ld
20-50°
4'3e
3. 3?
25'° b
12.8-25.8°
IP LD50
(ml/Kg)
oa
2'-5c
2.2C
3'8a
5.2a
6.0a
5.1a
d
50. Oa
100. 0C
Species
Rat
Rat
Mouse
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Mouse
Rat
Rat
Rat
Mouse
Gaunt et al. (1969) tested the acute toxicity of dialkyl 79
adipate (ester of adipic acid and a mixture of alcohols with 7-9
carbon atoms) in rats and mice. The oral LDso in mice was between
8 and 12 g/kg; 20 g/kg administered orally to rats produced
diarrhea as the only symptom. (Dialkyl 79 adipate is used
as a plasticizer for PVC.)
23
-------
Subacute Toxicity
The subacute toxicity of di(2-ethylhexyl) adipate has
been tested by several investigators. Fassett (1963) reported
a study in which rats were fed diets containing 0.5, 2.0, or
5.0% DOA (approximately 250, 1,000, or 2,500 mg/kg/day for
about a month) and were without effect except for growth
retardation at the 5% level. The same study found only a
transient loss of appetite in dogs fed 2 g/kg/day of DOA for
2 months.
Smyth et al. (1951) fed DOA to rats at doses ranging
from 0.16-4.74 gAg/day for 30 days. The investigators
found altered organ weights and a reduction in appetite and
growth in rats receiving 2.92 g/kg daily. Doses of 4.74
g/kg were subacutely lethal, while 9.11 g/kg was acutely
fatal. The no-effect dose was 0.6 g/kg.
Dialkyl 79 adipate was fed to rats at 0.0, 0.125, 0.25,
0.5, or 1.0% of the diet (approximately 0, 63, 125, 250, or
500 mg/kg/day) for 98 days. No effects were seen at or
below 0.25% of the diet. At the 1.0% level, weight gain was
lower in females, the relative kidney weight increased in
both sexes, and the hemoglobin concentration was reduced,
also in both sexes. In the 0.5% group, females displayed an
increase in relative kidney weight (Gaunt et al., 1969).
Environmental Aspects
MITRE Corp. (1976) estimates that 39.4 million Ib of
di(2-ethylhexyl) adipate was released to the environment in
1972.
Di(2-ethylhexyl) adipate has been identified at a
concentration of 30 ppb in the Monatiquot River in Massa-
chusetts. This is apparently the first time that an adipate
plasticizer has been identified in water and indicates that
plasticizers in addition to phthalates (which are recognized
widespread environmental contaminants) are entering the
aqueous environment (Kites, 1973).
The biodegradability of three adipate esters was deter-
mined in acclimated, activated sludge systems. Rapid primary
degradation (67-99+%) was observed at 3 and 13 mg/1 feed
levels for di(2-ethylhexyl) adipate, di-n-hexyl adipate, and
hexyl nonyl adipate over a 24-hr period (Saeger et al.,
1976) .
The phytotoxic effects of gases emitted by PVC plastic
covering materials were tested on various vegetable crops.
Among 25 plasticizers tested, diisobutyl phthalate and di(2-
24
-------
ethylhexyl) adipate were the most injurious to vegetable
plants. These plasticizers were apparently volatilized to a
phytotoxic degree from the plastic sheets under "normal"
conditions (Inden and Tachibana, 1975).
Several studies (Rubin, 1973; Easterling et al., 1974)
have demonstrated the migration of di(2-ethylhexyl) adipate
from plastic biomedical devices into blood. Up to 4 mg of
DOA was extracted from "medical grade" PVC tubing by human
plasma circulated for 6 hr at 37°C. DOA was also found in
blood stored in plastic packs.
REFERENCES
CEH (Chemical Economics Handbook). Menlo Park, Calif.,
Stanford Research Institute. 1976.
CCD (Chemical Dictionary). 9th ed. New York, Van Nostrand
Reinhold Co. 1977.
Darby, J. R., and J. K. Sears. Plasticizers. In Kirk-
Othmer Encyclopedia of Chemical Technology, vol. 15. New
York, Interscience Publishers. 1968. p. 720.
Easterling, Ronald E. et al. Plasma extraction of plasti-
cizers from "medical grade" polyvinylchloride tubing (38389)
Proc. Soc. Exp. Biol. Med. 147;572, 1974.
Fassett, David W. Esters. Iri Frank A. Patty (ed.) , Indus-
trial Hygiene and Toxicology, vol. II. New York, Inter-
science Publishers. 1963. p. 1890.
Gaunt, I. F. et al. Acute (rat and mouse) and short-term
(rat) toxicity studies on dialkyl 79 adipate. Food Cosmet.
Toxicol. 7^:35, 1969.
Kites, R. A. Analysis of trace organic compounds in New
England rivers. J. Chromatogr. Sci. 1_1(11):570, 1973.
Inden, T., and S. Tachibana. Damage on crops by gases
emitted from the plastic materials for covering. Mie
Daigaku Mogakuba Gakujutsu Hokoku. 5_0_:1, 1975. (Summary)
MITRE Corp. Scoring of Organic Air Pollutants: Chemistry,
Production, and Toxicity of Selected Synthetic Organic
Chemicals. September 1976.
Modern Plastics Encyclopedia, 52(10A). New York, McGraw-
Hill. 1975.
25
-------
Rubin, R. J. Biomedical implications of the migration of
phthalate ester plasticizers from PVC plastic. Tech. Pap.,
Reg. Tech. Conf. Soc. Plast., March 20-22, 1973, 81.
(Abstract)
Saeger, V. W. et al. Activated sludge degradation of adipic
acid esters. Appl. Environ. Microbiol. 3_1(5):746, 1976.
Singh, A. R. et al. Embryonic-fetal toxicity and terato-
genic effects of adipic acid esters in rats. J. Pharm. Sci.
6,2(10) :1596, 1973.
Singh, A. R. et al. Dominant lethal mutations and antifer-
tility effects of di-2-ethylhexyl adipate and diethyl adi-
pate in male mice. Toxicol. Appl. Pharmacol. 3^:566, 1975.
Smyth, Henry F. et al. Range-finding toxicity data: List
IV. Arch. Ind. Hyg. _4:119, 1951.
Smyth, Henry R. et al. Range-finding toxicity data: List
V. Arch. Ind. Hyg. 10.: 61, 1954.
U.S. EPA. Toxic Substances Control Act Chemical Substance
Inventory, Office of Pesticides and Toxic Substances, Wash-
ington, D. C.
26
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CHEMICAL HAZARD INFORMATION PROFILE
Aluminum and Aluminum Compounds
Date of report: September 1, 1976
This group of compounds was chosen for study because of
its high production volume and high exposure potential.
Aluminum is not recommended for further priority evalu-
ation within OTS at this time. None of the available infor-
mation indicates that aluminum may present a hazard to
humans or to the environment.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and avail-
able reference documents. Because of the limitations of
such sources, it necessarily follows that this report may
not reflect all available information on the subject chemical,
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Aluminum is the most abundant metal and third most
abundant element, making up 7.5% of the earth's crust. The
atomic number of aluminum is 13 and the atomic weight is
26.98. The melting point is 660°C and the boiling point is
2,327°C. Aluminum's density is 2.7 g/ml. Aluminum is an
excellent thermal and electrical conductor and is highly
resistant to most corrosive agents, aided by the formation
of a thin protective film of oxide on exposure to the
moisture in air. In its pure form, aluminum is a silvery
white metal with the highest reflectivity of any metal in
the visible and ultraviolet spectra. Pure aluminum is very
malleable and ductile, and many alloys with copper, zinc,
silicon, manganese, and magnesium are produced for various
commercial applications.
Aluminum does not exist naturally in the elemental
form, but is a constituent of many minerals, both rare and
abundant. Aluminum oxide, A1203, exists naturally in many
forms, including the precious stones sapphire, ruby, and
emerald and the minerals bayerite, bohemite, diaspore,
gibbsite, and corundum. The minerals differ primarily in
their degree of hydration and crystal structure, and are
27
-------
often grouped under the collective term bauxite. They are
water insoluble and increase in density from 2.4 to 4.0 g/ml
as the water content decreases from the trihydrate to the
anhydrous form. Corundum, the natural form of anhydrous
aluminum oxide, has a hardness of 9 on the Mohs scale as
compared with 1 for graphite and 10 for diamond, and finds
widespread applications as an abrasive. Other naturally
occurring aluminum minerals include albite, NaAlSi-jOR;
amonthite, CaAl2Si2Og; biotite and muscovite, complex micas;
cryolite, Na.~AlF,; kaolinite, Al.Si.O n(OH)_; orthoclase,
KAlSi3Og; and spinel, MgAl204.
Most inorganic aluminum compounds are white or color-
less crystals that are sparingly soluble in water and insol-
uble in ethanol. The organic salts tend to be yellowish
solids that are readily soluble in water and organic sol-
vents. Aluminum halides and hydrides are violently reactive
with water and generally soluble in nonpolar organic sol-
vents. Most aluminum salts possess astringent and antisep-
tic properties.
Organoaluminum compounds are highly reactive liquids.
Those in the lower alkyl series are spontaneously flammable
in air unless diluted to 25% or less with organic solvents.
All types are highly pyrophoric and will react with any
source of active hydrogen.
A complete list of commercially important aluminum
compounds is given in "Aluminum Compounds and Uses."
Production and Use
Bauxite is the starting material for the commercial
production of refined aluminum oxide, known commonly as
alumina, and aluminum metal. Most of the bauxite processed
in the United States is imported, chiefly from Jamaica and
Surinam. Virtually all domestic bauxite is mined in Arkansas.
Alumina is prepared by dissolving the bauxite in aqueous
NaOH to form soluble sodium aluminate. After removing the
insoluble impurities, the solution is cooled and aluminum
hydrate is precipitated by seeding. The aluminum hydrate is
collected and calcined at 1,200°C, yielding alumina. This
is known as the Bayer process.
Metallic aluminum is produced commercially by the
electrolytic reduction of pure aluminum oxide in a bath of
molten cryolite (SNaF'AlF-j) . Synthetic cryolite is cur-
rently used, due to depletion of the natural supply. It
takes 2.26 tons of dry bauxite to yield 1 ton of pure Al_0~,
and 1.817 tons of pure Al-O., is necessary for the production
of 1 ton of the pure metal.
28
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Aluminum is also recovered from old and new scrap aluminum,
aluminum alloys, and aluminum chemicals for secondary production.
Aluminum sulfates and other chemicals are generally produced
directly from bauxite or other aluminum minerals by conversion
with acids. More highly purified chemicals can be produced from
alumina. Aluminum chloride can be produced by mixing alumina and
hyprochlorous acid, but the chief mode of production is by
reacting molten aluminum metal with chlorine gas.
Alkyl aluminum compounds are prepared by direct synthesis
using the appropriate alkyl compounds and aluminum hydride, A1H3/
prepared by reacting powdered aluminum metal with hydrogen. Due
to the present availability of cheap olefins, this synthesis is
economical on a large scale.
Figure 1 shows the production pathways for aluminum
compounds. Available production and consumption data for
aluminum compounds are given in Tables 1 and 2.
Aluminum Compounds and Uses
Bauxite; Starting material for other aluminum compounds; can
also be utilized without further chemical conversion in
production of abrasive materials and refractory fire brick.
Aluminum metal; Structural material for diverse applications,
food processing apparatus, reducing agent in thermite process to
obtain other metals from their oxides.
Aluminum sulfate
and
Other aluminum compounds
Aluminum chloride
(Synthetic cryolite)
' I
Aluminum metal •
I
Organo-aluminums
Figure 1. Production of Pathways of aluminum compounds.
(Source: SRI, 1976)
T«61. 1. Uuxiu Production tnd CeMuapeion St«ci«ti=« (million! at toail
11.3. production laporti
ror
aluaiaa
dlr.otly
turn
1X0
1X1
1962
1X1
1X4
1X9
19K
1X7
1941
1949
1970
1971
1972
1973
1974
1,991
1,221
1,369
1,525
1,601
1,654
1.794
1,694
1.669
1,143
2,012
1,911
1,112
1.179
1,94>
1,739
9,20<
10,175
9,212
10,180
11,199
11,921
11,394
10,976
12,160
12,620
12,326
11,421
12,77«
14,301
1,141
a, 034
9,171
10.596
11.7«9
12.622
13,101
13,570
13,165
14,574
14,611
14,631
14,339
15.509
15,644
304
234
244
249
255
261
294
306
326
111
307
319
214
313
341
Mr«ilv«i Mirictorv
214
111
261
230
240
266
296
24<
223
254
210
207
213
2S9
295
94
112
131
179
219
291
313
111
111
J66
J70
310
403
496
539
(SOUTC.I SHI. 19761
29
-------
Table 2. Production of Aluminum and Aluminum Chemicals
(millions of tons)
Primary
aluminum
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
2,014
1,904
2,118
2,313
2,553
2,755
2,986
3,269
3,255
3,793
3,976
3,925
4,122
4,529
Secondary
aluminum
329
340
462
506
552
641
693
698
817
901
781
816
946
1,038
U.S.
alumina
3,896
3,699
4,402
4,817
5,319
5,577
5,884
6,046
5,859
6,672
6,563
6,445
6,204
6,785
Alumina
imports
«• «
—
—
—
__
227
488
952
1,316
1,887
2,555
2,175
2,850
3,375
Aluminum
chloride
31.2
28.8
31.7
32.6
38.0
40.6
42.9
44.0
42.4
46.2
37.8
34.7
__
--
Aluminum
sulfate
533
541
563
576
610
642
679
665
716
758
723
722
798
845
Aluminum Compounds and Uses
Bauxite; Starting material for other aluminum compounds; can also
be utilized without further chemical conversion in production of
abrasive materials and refractory fire brick.
Aluminum metalt Structural material for diverse applications,
food processing apparatus, reducing agent in thermite process to
obtain other metals from their oxides.
Alumina (aluminum oxide, A1203): Intermediate for aluminum metal
and other aluminum compounds, calcined for abrasive materials,
refractory brick for high-temperature furnaces, ceramics,
absorbent, drying agent, catalyst for organic chemistry, cos-
metics, pigments, paper coatings, electronic equipment, filler
in plastics and resins.
Aluminum sulfate; Antiperspirant, water purification, mordant
In dyeing,lubricating compositions, tanning, deodorizer and
decolorizer, ore flotation, cosmetics, Pharmaceuticals, pig-
ments, paper sizing.
Ammonium, potassium, and sodium alum; Baking powder, medicine,
mordant in dyeing^dressing of hides, water purification, paper
sizing.
30
-------
Aluminum hydroxide; Absorbent, catalyst, ceramics, mordant
in dyeing, paper sizing, water purification, waterproofing,
cosmetics, medicinals.
Aluminum chloride; Catalyst for organic reactions, cos-
metics, antiperspirant, antiseptic, wool carbonizing, photo-
fixing baths, wood preservative.
Sodium aluminate; Paper sizing, water treatment, cleaning
compositions, mordant in dyeing, sewage treatment, clarifi-
cation of sugar, welding fluxes, delustering of rayon,
enamel slips.
Aluminum phosphate; Organic catalyst, ceramics, glass
manufacture, dental cements, high-temperature bonding agent
for refractories.
Aluminum fluoride; Production of aluminum metal, ceramics,
repressant of alcoholic side fermentations, organic catalyst.
Triethyl aluminum, triisobutyl aluminum, diisobutyl aluminum
hydride"; Polymerization cocatalysts for production of
polyolefins, reducing agents, initiators for syntheses of
linear alpha-olefins and linear primary alcohols.
Aluminum acetate solution; Astringent, antipruritic,
antiseptic.
Aluminum bis(acetylsalicylate); Analgesic, antipyretic.
Aluminum borate; Polymerization catalyst, glass manufacture.
ture.
Aluminum borohydride; Reducing agent, preparation of other boro-
hydrides," jet and rocket fuel additive.
Aluminum bromide; Acid catalyst in organic synthesis.
Aluminum calcium hydride; Reducing agent.
Aluminum carbide; Generating methane, reduction of metal
oxides, manufacture of aluminum nitride.
Aluminum chlorate; Antiseptic, astringent.
Aluminum diacetate; Manufacture of color lakes, water-
proofing and fireproofing fabrics, antiperspirant, disin-
fectant.
Aluminum ethoxide; Reducing agent, polymerization catalyst.
31
-------
Aluminum hydride; Polymerization catalyst, reducing agent,
preparation of other metal hydrides.
Aluminum hydroxychloride; Astringent, antiperspirant.
Aluminum isopropoxide: Organic syntheses, manufacture of
aluminum soaps, paints, and textile waterproofing.
Aluminum lactate; Foam fire extinguishers, dental impres-
sion materials.
Aluminum lithium hydride; Reducing agent, preparation of
other hydrides.
Aluminum nitrate; Leather tanning, antiperspirant, corro-
sion inhibitor, uranium extraction, nitrating agent.
Aluminum oleate; Lacquer for metals, sizing agent, water-
proofing, high-temperature grease.
Aluminum palmitate; Thickening agent for lubricants, water-
proofing, sizing and glazing paper and leather.
Aluminum silicate; Dental cements, glass manufacture,
manufacture of semiprecious stones, enamels, and ceramics.
Health Aspects
Aluminum is present in plant and animal matter and is
used in food processing apparatus and containers; as a result
amounts of up to 200 mg are estimated to be ingested daily
by humans (Campbell et al., 1957). Aluminum is not readily
absorbed through the intestine, and only trace amounts
appear in tissues (Campbell et al., 1957). Ondreicka and
his associates (1966) found that rats fed a diet containing
2,835 ppm aluminum retained 20 times as much aluminum as
those fed a normal diet. Accumulation was highest in the
skeleton, liver, adrenals, and testes. Chronic dosing of
rats and mice at 350 ppm in diet caused growth stunting in
the second and third generations. Additional effects of
chronic and acute aluminum poisoning were interference with
intestinal phosphate absorption and inhibition of phosphoryla-
tion mechanisms for incorporation of phosphorus into DNA,
RNA, ATP, and phospholipids (Ondreicka et al., 1966). High
levels of dietary aluminum may also cause rickets due to the
movement of bone phosphorus to the serum to counteract the
decreased availability of ingested phosphorus (Underwood,
1973) . High doses of aluminum hydroxide, as used for an
antacid or in therapy for renal caliculi, produce no symp-
toms other than mild gastrointestinal irritation (Campbell
32
-------
et al., 1957). The disruption of phosphate metabolism is a
potential cause for alarm, and extensive removal of phosphate
from bones could seriously weaken susceptible individuals,
but no symptoms of toxicity are produced from normal dietary
intake of aluminum.
Aluminum salts have long been the substances of choice
in antiperspirant solutions. Solutions of 5% AlCl., (Lands-
down, 1974) and 10% A12(NO ) (Landsdown, 1973) applied to
the skin of mice, rabbits, and pigs caused dermal irritation
due to the affinity of the Al+3 ion for skin keratin in acid
solutions. Compounds showing no irritancy, except to highly
sensitive skin, include 25% solutions of aluminum chlorhydrate
(the most extensively used antiperspirant) and 10% solutions
of aluminum hydroxide, acetate, and sulfate (Landsdown,
1973) . The mechanism of the antiperspirant activity is not
understood.
The effects of inhalation of aluminum dusts and powders
are not completely understood. Goralewski (1947) reported
acute pulmonary degeneration in workers in an aluminum
powder stamping mill, with extensive pulmonary fibrosis in
several cases. The powders were coated with mineral oils to
prevent aggregation. Pulmonary fibrosis has also been
reported in England in workers exposed to stearin-coated
powders (McLaughlin et al., 1962; Mitchell et al., 1961).
Fibrosis has been reported in rats injected intratracheally
with fine aluminum dusts, both coated and uncoated, but not
with granular dusts (Corrin, 1963). These observations are
countered by studies by Crombie and associates (1944), who
found that workers in an aluminum stamping mill in Pitts-
burgh had as good health as any others in the plant.
Crombie et al. also experimented with aluminum powder as
treatment for silicosis. Of 34 men receiving 200-300 treat-
ments with the powder, 19 showed clinical improvement in
breathing capacity, while the condition of the other 15
stabilized. Fine metallic aluminum powders inhaled by
hamsters, rats, and guinea pigs caused no fibrosis, but
reversible alveolar proteinosis was present in all species.
Intratracheal injection did produce focal pulmonary fibro-
sis, an effect which was probably due to physical irritation
from this mechanism of exposure (Gross et al., 1973). Some
of the discrepancies in the reported effects could be due
to the different types of powders and different coatings
that have been investigated, but harmful effects seem obvious,
even if only mechanical. Other lung afflictions have been
reported from exposure to various dusts in the aluminum
industry, but since most aluminum minerals contain silicates
as well as alumina, the causative mechanisms are unclear.
33
-------
The American Conference of Governmental Industrial
Hygienists (1974) rates A120_ an inert particulate, with a
TLV of 3 million particles per cubic foot. No exposure
limit for airborne aluminum metal has been established. In
view of the conflicting evidence and the many unquestionable
dangerous effects reported, it cannot be denied that inhaled
aluminum powders are potentially debilitating and conditions
producing them should be strictly monitored.
Metallic aluminum has been tested for carcinogenic
activity, with no tumors resulting (Furst, 1971).
Alkyl aluminum compounds are extremely dangerous.
Contact with skin produces immediate deep painful burns.
Inhalation of vapors is destructive to lung tissue, and the
fumes of the combustion products are also toxic. All these
materials present a serious hazard to human health.
Aluminum in water at concentrations of over 1.5 ppm
causes physiological and behavioral aberrations and acute
mortality in rainbow trout (Freeman and Everhart, 1971).
A1C13 at 44 ppm in seawater is harmless to marine organisms,
88 ppm is fatal to most fish, and 132 ppm is universally
lethal to all organisms except sporulative bacteria (Pulley,
1950).
Aluminum chloride hexahydrate has been evaluated for
toxicity to goldfish and the narrowmouth toad. One ppm
(expressed as aluminum, in water pH 7-8) was the LC
concentration for newly hatched goldfish, while 75 ppm was
lethal to all individuals. Four days after hatching, the
LCgQ for goldfish was 0.5 ppm and the LCiQQ was 5 ppm, with
some anomalous effects appearing in the 0.001- to 0.01-ppm
range. Tests on newly hatched toads gave an LCsg value of
0.1 ppm and an LC^oO value of 10 ppm. Four days after
birth, the LCso was between 0.05 and 0.1 ppm and the LC^gO
about 0.5 ppm, with anomalous effects occurring at concentra-
tions between 0.01 and 0.05 ppm. Most of these values are
within the natural range for dissolved aluminum and place
the toxicity of aluminum about equivalent to that of zinc;
that is, less toxic than cadmium or mercury, but more toxic
than selenium or arsenic (Black, 1976).
Aluminum is present in all soils from the decomposition
of clays and other aluminum-containing minerals. At low pH
it is present as the free trivalent ion. As the pH rises
past 4, it begins to precipitate out as hydroxide. In the
presence of phosphate, solubility is further decreased, with
virtually complete precipitation by pH 4.4. In alkaline
conditions (pH > 8), aluminum reappears in solution, but
this does not represent any actual environmental conditions.
34
-------
Many studies have demonstrated the toxic effect of aluminum on
plants at soil pH values below 5. Potatoes grown in medium with
aluminum concentrations above 5 ppm showed reduced vegetative
growth and lower total tuber production by weight (Lee, 1971).
Dry plant matter production from several grasses grown at soil
concentrations of aluminum higher than 100 kg/hectare decreased
significantly in similar studies using soils of varying acidity
(Hutchinson and Hunter, 1970). The toxic effects are exhibited
most markedly in roots as elongation is sharply curtailed
(Rorison, 1958; Clarkson, 1966). Possible mechanisms for this
effect include phosphate starvation due to precipitation of
aluminum phosphates in the soil or in cell-free spaces in
the roots (Rorison, 1958) , direct inhibition of mitotic
division in the root tip (Clarkson, 1966), or the loss of
elasticity in the cell walls due to the aluminum-induced
precipitation of pectins (Rorison, 1958). Liming of soil to
pH 6 reduces the aluminum solubility to a point where it no
longer affects plant growth (Hutchinson and Hunter, 1970) .
Environmental Aspects
In the Bayer process of purifying alumina, large amounts
of Al.,0- dust are released. Because of the economic value
of these particulates, efficient control procedures including
multiple cyclones, electrostatic precipitators, and wet
scrubbers are used. In the electrolytic reduction of alumina
to aluminum, various gaseous and solid fluorides as well as
other particulates, depending on the type of cell used, are
produced. The gaseous effluents are fairly efficiently
controlled by such techniques as spray towers and floating
bed scrubbers, as well as a pathway in which the alumina
feed adsorbs the fluorides, which then reenter the reduction
bath. These techniques, plus cyclones, also remove most of
the particulates. The degree of efficiency of these systems
is largely determined by how well the effluent gases from
the cell can be contained, and cell types best adapting
themselves to these controls are being favored. Most of the
emissions are returned to the production process, although
some, especially fluorides, may appear in wastewater.
Alum and aluminum sulfate have been used as coagulants
and clarifying agents in water treatment facilities, resulting
in precipitation of 80% of the bacteria in organic matter.
Dissolved aluminum concentrations are usually lowered in
waters treated by these methods (Campbell et al., 1957).
Other sources of aluminum in wastewater include mining
operations, the chemical industries, the dye and pigment
industries, paper mills, textile plants, and dyeing and tanning
factories. Because of the very low solubility of aluminum
hydroxide at normal pH levels, almost all aluminum ions entering
the water systems will promptly precipitate out as the hydroxide.
This situation may lead to increased localized deposits of
35
-------
aluminum hydroxide, but there are no data which show that this
occurs. Monitoring of various water systems has shown that the
aluminum content of drinking water rarely exceeds 1 ppm and is
more likely to be below 0.5 ppm. Waters from mine drainage
contain no higher levels, but weathering of rocks with acid
waters can give levels of 10-20 ppm. Acid mineral springs may
contain several hundred ppm. These levels would apparently
present potential dangers to sensitive fish such as rainbow
trout, but no incidents of fish kills due to aluminum have been
reported.
Use of recyclable aluminum beverage cans is a viable alter-
native to the use of reusable bottles for prevention of solid
waste problems. In 1974, 2.3 billion cans worth about $13
million were returned for reprocessing. This was estimated
at about 35% of the aluminum cans produced. To be competitive
with reusable bottles, a recycling program would need to return
about 90% of the cans, indicating that more public cooperation
in this area will be necessary since without effective
recycling programs, aluminum cans are a solid waste problem
themselves.
Organoaluminum compounds cannot exist in the environment
since their extreme reactivity would result in immediate
destruction upon contact with air or water. The stringent
care necessary for safe handling of these materials in
industrial use also serves to prevent their release.
REFERENCES
American Conference of Governmental Industrial Hygienists.
Documentation of the Threshold Limit Values. 1974.
Black, Jeffery. University of Kentucky, personal communication.
1976.
Campbell, I. R., J. S. Cass, J. Cholak, and R. A. Kehoe. Aluminum
in the environment of man. AMA Arch. Ind. Health 15;359-448,
1957.
Clarkson, D. T. Aluminum tolerance within the species Agrostis.
J. Ecol. 5_4:167-178, 1966.
Corrin, B. Aluminum pneumoconiosis. II. Effect on the rat lung
of intratrachear injection of stamped alumina powders contain-
ing different lubricating agents and a granular aluminum
powder. Br. J. Ind. Med., vol. 20, 1973. (As cited by Gross
et al., 1973)
36
-------
Crombie, D. W., J. L. Blaisdell, and G. MacPherson. The treat-
ment of silicosis by aluminum powder. Can. Med. Assoc. J.
50; 318-328, 1944.
Freeman, R. A., and W. H. Everhart. Toxicity of aluminum
hydroxide complexes in neutral and basic media to rainbow trout.
Trans. Am. Fish Soc. 100 (4);644-658, 1971.
Furst, A. Trace elements related to specific chronic diseases:
Cancer. Geol. Soc. Am. Memoir 123:109-130, 1971.
Goralewski, G. Arch. Gewerbepathol. Gewerbe Hyg., vol. 9-11, 17,
1939-41, 1943.
Gross, P., R. Harley, and R. A. deTreville. Pulmonary reaction
to metallic aluminum powders. Arch. Environ. Health 26(5);227-
236, 1973.
Hutchinson, F. E., and A. S. Hunter. Exchangeable aluminum
levels in two soils as related to lime treatment and growth
of six crops species. Agron. J. £2_(6) :702-704, 1970.
Industrial Hygiene and Toxicology. New York, Interscience
Publishers. 1963.
Jones, H. R. Pollution Control in the Nonferrous Metals
Industry. Park Ridge, N.J., Noyes Data Corp. 1972.
Kirk-Othmer Encyclopedia of Chemical Technology. New York,
Interscience Publishers. 1974.
Landsdown, A. B. G. Aluminum compounds in the cosmetics
industry. Their action as antiperspirants and safety in
use. Soap Perfume Cosmet. £7^(5) : 209-212, 1974.
Lee, C. R. Influence of aluminum on plant growth and tuber
yield of potatoes. Agron. J. £3_(3) : 363-364, 1971.
McLaughlin, A. L. G. et al. Pulmonary fibrosis and encephalopathy
associated with the inhalation of aluminum dust. Br. J.
Ind. Med., vol. 19, 1962. (As cited by Gross et al., 1973).
Mitchell, J. Pulmonary fibrosis in workers exposed to
finely powdered aluminum. Br. J. Ind. Med., vol. 18, 1961.
(As cited by Gross et al., 1963).
Ondreicka, R., E. Ginter, and J. Kortus. Chronic toxicity
of aluminum in rats and mice and its effects on phosphorus
metabolism. Br. J. Ind. Med. 23:305-312, 1966.
37
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Perry, K.M.A. Diseases of the lung resulting from occupational
dusts other than silica. Thorax 2_: 91-120, 1947.
Pulley, T. E. The effect of aluminum chloride in small con-
centrations on various marine organisms. Tex. J. Sci. 2_(3) :
405-411, 1950.
Rorison, I. H. The effect of aluminum on legume nutrition.
Proc. Univ, of Nottingham Easter School of Agr. Sci. 5_: 43-61,
1958.
Stanford Research Institute. 1976. Chemical Economics Handbook,
Menlo Park, Calif.
Underwood, E. J. Trace elements. Toxicants Occurring Naturally
in Food 2_: 43-87, 1973.
Water Quality Criteria Data Book, Vol. 2. Inorganic Chemical
Pollution of Freshwater. Cambridge, Mass., Arthur D. Little,
Inc. 1971.
38
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CHEMICAL HAZARD INFORMATION PROFILE
Aniline
Date of report: January 20, 1978
This chemical was chosen for study because of its high
production volume.
It is recommended that OTS wait for completion of the
scheduled NIOSH Criteria Document and the NCI carcinogenicity
study before initiating any further evaluation of aniline.
This CHIP should be updated based on the additional informa-
tion.*
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Aniline (phenylamine, aminobenzene) is a colorless,
oily liquid having a boiling point of 184 C. Aniline is
miscible with alcohol, benzene and chloroform; it is soluble
in water (Stecher, 1969; Weast, 1971).
Production and Use
Aniline is produced commercially by the reduction of
nitrobenzene or the ammonolysis of chlorobenzene (Lowenheim
and Moran, 1975). Annual domestic production of aniline is
currently around 500 million Ib. The major producers of
aniline are American Cyanamide Co. (two plants; West Virginia
and New Jersey), E. I. du Pont de Nemours (two plants; Texas
and New Jersey), First Mississippi Corp. (one plant; Mississippi)
and Rubicon Chemicals, Inc. (one plant; Louisiana) (SRI,
1977).
*Subsequent to the review of this CHIP document and the
selection of the tentative dispositions given above, the
TSCA Interagency Testing Committee recommended aniline for
primary consideration for possible testing under section
4(a) of TSCA (44 FR 31866, June 1, 1979).
39
-------
Table 1. Aniline Consumption Pattern (%)
Isocyanates 40
Rubber chemicals 35
Dyes and intermediates 6
Hydroquinone 4
Drugs 4
Miscellaneous 9
Source: SRI, 1977.
As can be seen from Table 1, aniline is most commonly
used as a chemical intermediate for the production of other
products. Miscellaneous uses of aniline include: production
of resins (formaldehyde, furfural, epoxy, and others);
corrosion inhibitor to protect some metals from attack by
wet carbon tetrachloride; manufacture of explosives, phenolics,
surfactants, herbicides, fungicides, diphenylamine, varnishes,
and perfumes; in textile, paper, metallurgical, and petroleum
refining industries; catalyst; stabilizer (especially as
polymerization inhibitor); intermediate in dye industry
(Stecher, 1969; CCD, 1977; Kouris and Northcott, 1967).
Health Aspects
Methemoglobinemia is the most prominent symptom of
aniline poisoning in man (Hamblin, 1963). The symptoms of
the toxic methemoglobinemia are those of oxygen lack proportional
to the percentage of hemoglobin that is tied up. Levels of
methemoglobin below 20% generally cause no symptoms; 20-50%
methemoglobin can result in dyspnea, tachycardia, headache,
and dizziness; concentrations above 60-70% may produce coma
and death (Harrison, 1977).
Inhalation of 7-53 ppm of aniline vapor causes only
slight symptoms of methemoglobinemia, while exposure to
concentrations in excess of 100-160 ppm for over 1 hr can
cause serious difficulty (Henderson and Haggard, 1943).
IARC (1973) reviewed the carcinogenicity data on aniline
and concluded that the presently available information
appears to indicate that aniline is not a human or animal
carcinogen. McCann et al. (1975) reported that aniline was
negative in the Ames test for mutagenicity.
40
-------
Environmental Aspects
MITRE Corp. (1976) , in an EPA-sponsored report, estimates
that 6.15 million Ib of aniline was released to the environment
in 1974. The U.S. production of aniline for that year
totaled 551 million Ib.
Aniline in the atmosphere reacts photochemically to form
N-methylaniline, N,N-dimethylaniline, acetanilide, isomeric
hydroxyanilines, and phenols (MITRE Corp., 1976). (The
first four compounds can cause methemoglobinemia in similar
fashion to that seen with aniline °Sax, 19751.)
In a model ecosystem, aniline (0.01-0.1 ppm) was rapidly
and completely detoxified to polar metabolites by Daphnia
and freshwater snails. Algae and mosquito larvae, however,
were found to retain N-methyl- and N,N-dimethylaniline,
respectively. Mosquito fish retained small amounts of
unchanged aniline (with ecological magnification) and other
metabolities (Lu and Metcalf, 1975).
Aniline is fairly toxic to nitrifying bacteria such as
Nitrosomas sp. and Nitrobacter sp. A concentration of 7.7
mg/1 of aniline inhibits nitrification in activated sludge
by approximately 75% (Tomlinson et al., 1966).
Aniline degrades readily in soil, as it has a half-life
of less than 1 week (Thompson, 1969).
REFERENCES
CCD (Condensed Chemical Dictionary), 9th ed. New York, Van
Nostrand Reinhold Co. 1977.
Hamblin, D. 0. Aromatic nitro and amino compounds. In F. A.
Pattv (ed.). Industrial Hvaiene and Toxicoloov. 2nd e3T New
York. Interscience Publishers. 1963. D. 2105.
Harrison. M. R. Toxic methemoalobinemia. Anaesthesia 22:270.
1977.
Henderson. Y., and H. W. Haaaard. Noxious Gases, 2nd ed. New
York, Reinhold Publishing Co. 1943. As cited in Documentation
of the TLV, ACGIH, 1971.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of the Carcinogenic Risks of Chemicals
to Man, vol. 4. 1973. p. 27.
Kouris, C. S., and J. Northcott. Aniline and its derivatives.
In Kirk-Othmer Encyclopedia of Chemical Technology, vol 2.
T§67. p. 411.
41
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Lowenheim, Frederick A., and Marguerite K. Morari. Faith,
Keyes, and Clark's Industrial Chemicals. New York, John
Wiley and Sons. 1975.
Lu, P. Y., and R. L. Metcalf. Environmental fate and biodegrada-
bility of benzene derivatives as studied in a model ecosystem.
Environ. Health Perspect. 1£:269, 1975.
McCann, Joyce et al. Detection of carcinogens as mutagens in the
Salmonella/microsome test: Assay of 300 chemicals. Proc.
Natl. Acad. Sci. U.S.A. 72(12):5135, 1975.
MITRE Corp. Scoring of Organic Air Pollutants. Chemistry,
Production, and Toxicity of Selected Synthetic Organic Chemicals.
1976. *
Sax, N. Irving. Dangerous Properties of Industrial Materials, 4th
ed. New York, Van Nostrand Reinhold Co. 1975.
SRI (Stanford Research Institute). Chemical Economics Handbook.
Menlo Park, Calif. 1977.
Stecher, P. G. (ed.). The Merck Index, 8th ed. Rahway, N.J.,
Merck and Co. 1969.
Thompson, F. R. Persistence and effects of some chlorinated
anilines on nitrification in soil. Can. J. Microbiol.
15_(7) :791, 1969.
Tomlinson, T. G. et al. Inhibition of nitrification in the
activated sludge process of sewage disposal. J. Appl.
Bacteriol. 2_9(2) :266, 1966.
Weast, Robert C. (ed.). CRC Handbook of Chemistry and
Physics, 52nd ed. Cleveland, Chemical Rubber Co. 1971.
*This document was prepared for the U.S. Environmental
Protection Agency by the MITRE Corp. It is a secondary source
and does not cite its primary references. Thus, verification
of some information is not possible. The environmental release
data were taken from the NSF/Rann Research Program on Hazard
Priority Ranking of Manufactured Chemicals.
42
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CHEMICAL HAZARD INFORMATION PROFILE
Benzyl Chloride
Date of report: December 9, 1977
This chemical was chosen for study because of its
relatively high production volume.
It is recommended that TSCA Section 8(a) and 8(d)
submissions be required for benzyl chloride. More definitive
information on exposure potential is needed as well as
additional information to supplement the relatively scanty
data on health effects. A contractor literature search on
environmental aspects is recommended because very little
information was found in the preparation of this report.
This Chemical Hazard Information Profile should be updated
based on the additional data obtained.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Benzyl chloride (C^-H^GH-Cl) is a colorless, highly
refractive liquid with a pungent aromatic odor. It freezes
at -39 C and boils at 179.4 C. The density of benzyl
chloride is 1.1002 at 20°C. The vapor pressure of benzyl
chloride is 1.4 mm at 25 C. It is immiscible in water, but
decomposes in hot water to give benzyl alcohol. At room
temperature it is miscible with ethanol, ether, and chloroform.
Its explosive limit in air is lower than 1.1% by volume. It
is considered a moderate fire hazard and a moderate explosion
hazard (violent with metals) (Lowenheim and Moran, 1975, and
other sources). Benzyl chloride is a dangerous disaster
hazard since it will react with water or steam to produce
toxic and corrosive fumes; it can react vigorously with
oxidizing materials (Sax, 1968). Synonyms for benzyl chloride
include alpha-chlorotoluene and alpha-tolyl chloride.
43
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Production and Use
The only processes in commercial use in the United
States for the manufacture of benzyl chloride are the direct
chlorination of boiling toluene in the dark and the photo-
chlorination of toluene. Boiling toluene is chlorinated in
the dark until there is a 37.5% increase in weight. The
reaction mixture is then agitated with mild alkali and
distilled. Benzal chloride and benzotrichloride are formed
as by-products of benzyl chloride in a ratio of 1:0.1:10.
In the photochlorination process, chlorination is continued
until a 20 to 25% weight increase in the reaction mixture is
achieved. Using this procedure, it is possible to avoid the
formation of benzotrichloride. In this case the ratio of
benzyl chloride to benzal chloride is 10:1 (Lowenheim and
Moran, 1975).
The still bottoms of benzyl chloride production are a
hazardous waste discharge to land disposal and contain 0.001
kg of highly dangerous components (benzyl chloride and
benzotrichloride) per kg of benzyl chloride produced (Gruber,
1976) .
The major commercial producers of benzyl chloride and
their capacities (as of December 1975) are:
Capacity
Producers (millions of Ib/yr)
Monsanto, Bridgeport, N.J. 75
Stauffer, Edison, N.J. 11
Tenneco, Fords, N.J. _9_
Total 95
Monsanto had plans to bring another benzyl chloride
plant on stream at East St. Louis, Mo. (Sauget, 111., according
to CEH, November 1976) in 1977 to feed a new benzyl butyl
phthalate plant. The plant capacity was expected to be at
least.75 million Ib per year. The annual demand for benzyl
chloride was 90 million Ib in 1975 (Chemical Marketing
Reporter, December 12, 1975). Benzyl chloride is available
commercially in an anhydrous form or stabilized with aqueous
sodium carbonate solution (Hawley, 1977).
Major uses of benzyl chloride are benzyl butyl phthalate,
67%; benzyl alcohol, 13%; quarternary amines, 12%; and other
uses, 8% (Chemical Marketing Reporter, December 12, 1975).
44
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Benzyl butyl phthalate is used as a plasticizer in the
manufacture of flexible vinyl, especially floor coverings.
Growth in demand for flexible vinyl, and hence for benzyl
butyl phthalate, is expected to continue. Benzyl alcohol is
used as a dye assist, as a photographic developer, and in
making Pharmaceuticals and perfumes. Benzyl chloride serves
as a raw material for disinfectants, bactericides, perfumes,
and Pharmaceuticals. Benzyl chloride may be used in synthetic
tannins and synthetic penicillin, as a gasoline gum inhibitor,
and as an intermediate in other processes. Benzyl chloride
is also used as an intermediate in the production of benzyl
acetate, benzyl cyanide, benzyl salicylate, and benzyl
cinnamate. Use of benzyl chloride as an irritant gas has
been reported (IARC, 1976) .
Health Aspects
The TWA established by OSHA for benzyl chloride in air
is 1 ppm. (Soviet standard for benzyl chloride in the work
place is 0.1 ppm [Hoecker et al., 1977].) The 96-hr aquatic
toxicity rating is 10 to 1 ppm. The LD for oral administration
of benzyl chloride is 1,231 mg/kg for rats and 1,624 mg/kg
for mice. Inhalation of benzyl chloride vapors by mice and
rats gives LC5Q values of 80 and 150 ppm, respectively, for
2 hr of exposure (NIOSH, 1976) . Reaction of guinea pigs to
dermal application of benzyl chloride indicates that it is a
strong sensitizing agent (Hoecker et al., 1977). Benzyl
chloride has been found to be weakly mutagenic in Salmonella
typhimurium (TA100) after treatment with 2 mg benzyl chloride
per plate in the Salmonella/microsome test (McCann et al.,
1975) .
Benzyl chloride is absorbed by the lungs and the digestive
tract. It appears to be metabolized to benzyl mercapturic
acid following injection in rats and rabbits and oral
administration in dogs. Following oral administration in
rabbits, it is excreted in the urine as mercapturic acid and
benzoic acid (IARC, 1976) .
Fourteen week-old rats were given subcutaneous injections
of 40 mg/kg benzyl chloride in arachis oil for 51 weeks.
Three animals developed local sarcomas within 50 days. Of
eight rats given 80 mg/kg benzyl chloride for 51 weeks, six
developed local sarcomas in 500 days.
Most animals also developed lung metastases. Injection
of arachis oil did not produce local tumors in control rats.
Based on this information, the IARC considers benzyl chloride
to be a carcinogen in rats.
45
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Mice given intraperitoneal injections of benzyl chloride
three times a week for 2 to 4 weeks (total dose of 600,
1,500, or 2,000 mg/kg) did not show significant changes in
tumor incidence (Hoecker et al., 1977).
The human TCLo for inhalation of benzyl chloride has
been found to be 16 ppm. This level of exposure was found
to be intolerable within 1 min (ACGIH, 1971). Benzyl chloride
is highly irritating to eyes, ears, nose, and throat and can
cause lung edema. It may depress the central nervous system
(ITII, 1976).
Environmental Aspects
Benzyl chloride contamination of aquatic environments
seems unlikely since it is reactive in water. Benzyl chloride
reacts with oxidizing agents (Dorigan et al., 1976). Benzyl
halides are considered very reactive, having a half-life
(hydrolysis) of only a few minutes. Benzyl chloride is
lipophilic as indicated by its log P value of 2.30 (Radding
et al., 1977).
REFERENCES
American Conference of Governmental Industrial Hygienists
(ACGIH). Documentation of the Threshold Limit Values.
1971.
Chemical Marketing Reporter, December 12, 1975.
Dorigan, J. et al. Scoring of Organic Air Pollutants:
Chemistry, Production and Toxicity of Selected Organic
Chemicals. MITRE Corp. (for EPA). 1976.
Gruber, E. I. (Project Manager). Assessment of Industrial
Hazardous Waste Practices, Organic Chemicals, Pesticides,
and Explosives Industries. U.S. Environmental Protection
Agency. 1976.
Hawley, Gessner G. Condensed Chemical Dictionary, 9th ed. New
York, Van Nostrand Reinhold Co. 1977.
*This document was prepared for the U.S. Environmental
Protection Agency by the MITRE Corp. It is a secondary source
and does not cite its primary references. Thus, verification
of some information is not possible. The environmental
release data were taken from the NSF/Rann Research Program on
Hazard Priority Ranking of Manufactured Chemicals.
46
-------
Hoecker, Jane E. et al. Information Profiles on Potential Occu
pational Hazards. Center for Chemical Hazard Assessment
(for NIOSH). 1977.
IARC (International Agency for Research on Cancer. IARC
Monographs on the Evaluation of Carcinogenic Risk of Chemicals
to Man, vol. II. Lyon, France. 1976. p. 217-221.
International Technical Information Institute (ITII). Toxic
and Hazardous Industrial Chemicals Safety Manual. Tokyo.
1976.
Lowenheim, Frederick, and Marguerite Moran. Faith, Keyes
and Clark's Industrial Chemicals, 4th ed. New York, John
Wiley & Sons, Inc. 1975.
McCann, Joyce et al. Detection of carcinogens as mutagens
in the Salmonella/microsome test: Assay of 300 chemicals.
Proc. Natl. Acad. Sci. U.S.A. 7_2 (12) : 5135-5139 , 1975.
NIOSH. Registry of Toxic Effects of Chemical Substances,
1976 ed.
Radding, Shirley B. et al. Review of the Environmental Fate
of Selected Chemicals. Stanford Research Institute (for
EPA). May 1977.
Sax, N. Irving. Dangerous Properties of Industrial Materials,
3rd ed. New York, Van Nostrand Reinhold Co. 1968.
Stanford Research Institute (SRI). Chemical Economics
Handbook. Menlo Park, Calif. 1976.
Stanford Research Institute. Directory of Chemical Producers.
Menlo Park, Calif. 1975.
47
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CHEMICAL HAZARD INFORMATION PROFILE
Bromine and Bromine Compounds
Date of report: November 1, 1976
This group of chemicals was chosen for study because of
a report describing damage to vegetation near bromine production
facilities.
It is recommended that this group of chemicals be
considered for further testing needs. The high potential
for the development of new bromine compounds and new uses
for old compounds is the impetus for testing consideration.
This report, represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
General Information, Production, and Consumption
Bromine belongs to the group of nonmetallic elements
known as the halogens, which includes fluorine, chlorine,
iodine, and the extremely rare element astatine. Elemental
bromine exists in the diatomic form, Br2, and it is a volatile
liquid at ordinary room temperature (boiling point 58.8 C
at atmospheric pressure). Bromine is a strong oxidizing
agent similar to but weaker than chlorine. The most stable
valence states of bromine are -1 and +5, although valence
states of +1 anc. +3 are also known.
Bromine is widely distributed in nature in both the
solid portion of the earth's crust (1.6 ppm) and in ocean
water (65 ppm by weight). Bromine is also abundant in the
waters of salt lakes found in closed basins and in the
brines or saline deposits left by the evaporation of such
salt lakes during earlier geologic periods. Brines serve as
the primary source of bromine in the United States; seawater
is used as a bromine source in other parts of the world but
not, at this time, in the United States.
48
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Eighty percent of the bromine produced in the United
States is extracted from natural brines in the El Dorado-
Magnolia area of southern Arkansas; most of the remainder is
produced in Michigan (see Table 1).
Table 1. Domestic Bromine Producers, Plant Locations,
and Capacities (1976)
Company
Arkansas Chemical Inc.
Dow Chemical USA
Ethyl Corp.
Great Lakes Chemical Corp.
Kerr-McGee Corp.
Morton-Norwich Products, Inc,
Northwest Industries, Inc.
Locations
El Dorado, Ark.
Ludd ington, Mich,
Magnolia, Ark.
Midland, Mich.
Magnolia, Ark.
El Dorado, Ark.
Marysville, Ark.
Trona, Calif.
Manistee, Mich.
El Dorado, Ark.
St. Louis, Mich.
Capacity
(10b Ib)
60
15
85
105
160
95
45
2
Unknown
25
5
Total
597
Source: CEH, 1976.
Bromine exists as the bromide ion in these brines, and
obtaining elemental bromine from them entails four essential
steps: oxidation of the bromide in the brine to bromine,
removal of bromine vapor from solution, condensation of the
vapor, and, finally, purification of the product. Initially
the brines are heated from the ground recovery temperature
of 90 C to just below the boiling point of 107 C. Chlorine
is added to oxidize the bromide ions and replace them in the
brine. The released bromine is separated from the brine by
"blowing out" with steam and is then purified by distillation
and dried with sulfuric acid. The chlorine is recycled, and
bromine recovery is generally in excess of 95% (Stenger,
1964; CEH, 1976).
Table 2 shows the annual production and consumption of
bromine for recent years. As can be seen from these data,
most of the elemental bromine is used to manufacture bromine-
containing compounds. The largest end use of bromine,
currently accounting for about 50-60% of bromine consumption,
49
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is for the production of ethylene dibromide (EDB), which is
used primarily as a lead scavenger in gasoline. In past
years, EDB has accounted for well over 90% of bromine consumption.
The decline in EDB use in recent years has been due largely
to the lowering of the lead content of gasoline and the
conversion to nonleaded gasoline for newer model cars. The
second largest end use of bromine is for the production of
methyl bromide, which is used as a pesticide, soil and grain
fumigant, and fire-extinguishing fluid.
The elemental bromine consumption data shown in Table 2
refer to that which is sold by primary producers. Some of
this is used directly for such applications as a bleaching
and disinfecting agent, swimming pool sanitation, and water
purification; some is sold to other companies to be used in
the production of bromine compounds.
The "Other" category in Table 2 includes the numerous
organic and inorganic bromine compounds that are produced by
too few companies for production data to be available from
the International Trade Commission. In addition to elemental
bromine itself, the major inorganic bromine compounds are
hydrobromic acid and the bromide salts (potassium, sodium,
and ammonium). Hydrobromic acid is used as an industrial
chemical for the production of other bromine compounds; the
alkalai bromides are used in the preparation of sedatives,
medicines, and photographic emulsions. The end use of
inorganic bromine compounds noted as having future growth
potential is that of water and waste treatment. Elemental
bromine, as noted above, and bromine chloride (BrCl) are the
bromine compounds likely to be important in such applications.
There are many organic bromine compounds, both aliphatic
and aromatic, which are available commercially for a variety
of applications, including uses as intermediates, agricultural
chemicals, photographic chemicals, dyes, inks, medicinals,
hydraulic fluids, coolants, cosmetics, and reagents. The
fastest growing end use for organic bromine compounds,
however, is in the area of fire- and flame-retardant chemicals.
Consumption of bromine for this end use has grown from 10
million Ib in 1964 to 56 million Ib in 1974, with the largest
growth in the most recent years. Some of these compounds
are used as fire-extinguishing agents (bromotrifluoromethane
and bromochlorodifluoromethane), some are used as monomers
for fibers, plastics, and foams (for example, tetrabromobisphenol
A and tetrabromophthalic anhydride), and some are simple
additives to synthetic resins (for example, tris[2,3-dibromopropyl 1
phosphate, though this compound is now being phased out).
50
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The most notable feature of the bromine industry at
this time is its changing character with respect to outlets.
The lack of market diversification in the past, when almost
all of the bromine produced was converted to EDB, is now
being overcome as the number of bromine compounds available
and the specific applications of these are on the increase.
The general trend appears to be toward continued, vigorous
growth, particularly in the flame retardants market, and
possibly significant growth in the area of water and waste
treatment.
Health and Environmental Problems
The following are brief discussions of the health and
environmental problems relating to bromine that appear, from
this preliminary investigation, to be of particular importance.
Bromism
"Bromism" is the clinical term for the condition associated
with excessive tissue levels of bromide ions. The symptoms
of bromism are subtle, though well established: slowing of
cerebration, impaired memory, anorexia, skin rash, headache,
slurring of speech, confusion (Campbell, 1949), weakness,
disturbed reflexes (Neiswander, 1958), drowsiness, and mild
conjunctivitis {Woodbury, 1972). The blood bromide concentration
needed to evoke the symptoms of bromism is dependent upon
the individual; severe reactions are known to occur with
bromide levels as low as 0.5 mg/ml of blood. Generally,
however, intoxications of 0.5-1.5 mg/ml of blood are deemed
moderate, while levels above 1.5 mg/ml are severe (Campbell,
1949).
The most common cause of bromism is the abuse of bromide-
containing patent medicines, although occupational exposure
(Shapovalov et al., 1974) and ingestion of well water with
high bromide levels (Fried and Malek-Ahmadi, 1975) may also
lead to the onset of the condition. Chronic exposure to a
bromide source, even at low concentrations, may lead to
bromism because of the long plasma half-life of the bromide
ion. Woodbury (1972) estimates that the half-life of the
ion in the human is at least 12 days. Ingested bromide ions
are preferentially retained by the kidneys at the expense of
chloride; thus chloride levels in the body are depressed in
direct proportion to the bromide elevation. For instance,
the CNS effects of bromism are traceable to bromide replacement
of chloride ions in the brain. Bromism, however, does not
result in permanent damage to the CNS or other body functions;
with removal of the bromide source, recovery is generally
rapid (Woodbury, 1972) .
52
-------
There is one instance reported in the literature of a
possible teratogenic effect associated with bromism. Opitz
et al. (1972) detail a woman who had two normal children
prior to a 5-year bout with bromism. During the period of
heaviest bromide intake, she had two boys who differed from
the two siblings born previously. The two boys were short
(second percentile for age) and had small heads (one was
definitely microcephalic), and the microcephalic child had a
congenital heart defect. Following this period, the woman
was taken off bromides and gave birth to a normal boy.
The metabolism of bromides is closely related to the
functioning of the thyroid gland in man. Bromide blocks the
entry of iodide into the thyroid and, with chronic bromide
administration, can lead to thyroid tissue hyperplasia,
better known as goiter. Several of the effects of bromism
are identical to those attributed to hypothyroidism.
Toxicity of Organic Bromine Compounds
Organobromines tend to exhibit greater toxicity than
inorganic bromine compounds. The effects associated with
organobromine compounds include damage to the CNS, male
reproductive system, kidneys, and liver. In addition,
several organic bromide compounds have been implicated as
mutagens and/or carcinogens.
A summary of the toxic effects of some common organic
bromides follows:
(1) Methyl bromide—chronic exposure to low levels can be
fatal due to CNS and kidney damage (Sax, 1968).
(2) Bromoform—has a narcotic effect similar to that of
chloroform, but is more toxic to the liver (Sax, 1968).
(3) Ethyl bromide-—less toxic than methyl bromide, but can
damage the liver and kidneys (Sax, 1968) .
(4) Ethylene dibromide (EDB)—affects the liver and kidneys
(Sax, 1968); has been shown to damage the male repro-
ductive system in bulls (Amir, 1973) and rats (Edwards
et al., 1970).
(5) 1,2-Dibromo-3-chloropropane (Nemagon, DBCP)—chronic
exposure leads to liver, kidney, and lung damage
(Gleason et al., 1969); has been shown to affect the
male reproductive system in rats (Gleason et al., 1969;
Faidysh and Avkhimenko, 1974).
53
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Nemagon and EDB are also known mammalian carcinogens (Olson
et al., 1973), while several organobromine compounds have been
found mutagenic:
(1) 1,2-EDB, 1,1-EDB, l-bromo-2-chloroethane, 1,5-dibro-
mopentane, l,2-dibromo-2-methylpropane, and 1,1,2,2-
tetrabromopentane in E. coli and S. typhimurium (Brem
et al., 1974).
(2) 1,2-EDB and 1,2-dibromopropane in Drospphila
melanogaster (Vogel and Chandler, 1974) .
Generally, organobromo compounds have greater mutagenic
and DNA-modifying activity than their chloro analogs (e.g.,
EDB > EDC). In addition, the biological activity is enhanced
when more than one bromine is attached to the same carbon
atom (1,1-EDB > 1,2-EDB). When the halogens are on different
carbons, however, the distance between the halogens has no
appreciable effect on the activity (Brem et al., 1974).
Bromine Phytotoxicity and Other Problems in Arkansas
As noted previously, most domestically produced bromine
is extracted from brines in the El Dorado-Magnolia area of
Arkansas. Bromine released as a consequence of these
production activities has had serious effects upon vegetation
in the locale. The first noted manifestation of a problem
was damage to coniferous trees near the bromine plants.
Needle tip necrosis after 13- to 14-month and 1- to 2-month
exposure times was very evident within a 3-mile radius of
all bromine facilities sampled. At further distances of 3.5
to 12 miles, tip damage was sporadic, varying from tree to
tree, and not evident on 1- to 2-month-exposure needles.
The foliage burn and death of trees, within 0.5 to 1 mile of
each plant site was extreme. Conifers were decidedly more
susceptible to the bromine emissions than were broadleaf
trees, shrubs, and grasses. Chlorophyll (a and b) levels
were greatly reduced in the conifer trees surrounding the
bromine plants. This was taken as a strong indicator of
extreme air pollution problems because chlorophyll does not
reflect environmental problems until they become overwhelming
(Gordon, 1976).
The evidence of vegetative damage prompted the initiation
of air-monitoring activities in the locality. Preliminary
results have shown the presence of several potentially
dangerous organobromine compounds in the air near the bromine
production sites.
54
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Bromine and Stratospheric Ozone
In the past few years, there has been increasing concern
over the depletion of the earth's protective stratospheric
ozone layer by various human activities. The reduction of
stratospheric ozone could have severe adverse effects on
climate, agriculture, and skin cancer rates. At the forefront
of this area, recently, has been the theory that certain
widely used chlorofluorocarbon aerosol propellants and
refrigerants are transported into the stratosphere by atmos-
pheric motions, where the chlorine atoms in the molecules
are released by photolysis. The chlorine then acts, through
a catalytic cycle, to destroy ozone molecules. It has also
been recognized that, like chlorine, any bromine entering
the stratosphere will also destroy ozone catalytically.
Furthermore, the bromine cycle is believed to be more efficient
in destroying ozone than is the chlorine cycle.
Many of the manmade bromine compounds do not appear to
be of significance to stratospheric ozone because of properties
or use patterns which would preclude their reaching the
stratosphere. Others have been identified as potential
problems, such as methyl bromide, for which Wolfsy et al.
(1975) have cautioned against unconstrained growth in use.
Still other compounds, now produced in too small a quantity
to be a significant threat (for example, the fire-extinguishing
agents bromotrifluoromethane and bromochlorodifluoromethane),
have properties which clearly indicate that they could, if
produced in larger amounts, be of serious concern.
Bromine Compounds in Water
One of the potential growth areas for bromine is in the
purification of drinking water. The switch from chlorine to
a bromine or bromine chloride water sanitation system is not
without possible health implications. Bunn et al. (1975)
found that the addition of KBr to natural Missouri River
water caused a substantial reduction in the chloroform
concentration while increasing the levels of bromodichloromethane,
dibromochloromethane, and bromoform found in the sample. As
noted earlier in this report, brominated compounds generally
display greater biological activity than their chlorinated
analogs. In view of this, any purification technique which
may increase the levels of brominated methanes in drinking
water should be carefully evaluated before being allowed to
come into operation.
Another aspect of this problem is the influence of
man's other activities on the bromine levels found in natural
surface waters. Bromine should be a conservative property
55
-------
of water (Skopintsev [1973] estimates bromine's half-life in
the Black Sea to be 1,800 years) and will not be efficiently
removed via biological or sedimentation processes. Tiffany
et al. (1969) report that the bromine concentration in the
Great Lakes has increased steadily with time as a consequence
of both pollution and natural processes. The major pollution
sources are auto emissions and industrial effluents.
A final problem with bromine concerns the naturally
occurring levels of bromine found in well waters. Fried et
al. (1975) speculate that some instances of bromism in rural
areas are actually due to bromide contamination of drinking
water. They cite the occurrence of 0.08% bromine in a soft-
water source in Kansas as an extreme example of what may be
a real, though unrecognized, problem.
Summary and Conclusions
Bromine is found naturally in the environment at relatively
low levels. As a consequence of human activities, however,
the concentration of bromine found in the ambient environment
has greatly increased. Most of this rise is due to bromine
released to the atmosphere following the combustion of
leaded gasoline, although other sources (industrial processes,
wastes, etc.) have contributed as well.
•
The long-term health and environmental implications of
elevated bromine levels, while not known with certainty, are
of some concern. The carcinogenic and mutagenic activity
associated with organobromine compounds represents the most
immediately evident of these concerns. The significance of
the other problem areas outlined in this paper is more
difficult to appreciate. Bromism, for instance, may occur as
the direct result of increased exposure to Br in air and,
particularly, water. Current exposure data, however, are
not available to assist in the delineation of the problem.
This, in combination with the subtle nature of bromism,
keeps the problem vague. The bromine-stratospheric ozone
situation, bromine as a water sanitizer, and the extent of
the Arkansas problem are also poorly defined. The information
gaps preclude any considered assessment of the significance
of each at this time.
Presently, bromine use and consumption patterns are
changing and thereby altering the nature of the anthropogenic
source. The declining demand for EDB is forcing the bromine
industry to find new outlets for the anticipated bromine
glut. Fire- and flame-retardant materials are currently
seen as one of the growing consumptive uses of bromine;
however, other product types must be developed before the
56
-------
bromine market will firm up. The anticipation is that TSCA
will play a large role in decisions as to the acceptability
of these new products and uses.
REFERENCES
Amir, D. Sites of spermicidal action of ethylene dibromide
in bulls. J. Reprod. Pert. 3_5 (3) : 519-525, 1973.
Brem, H., A. B. Stein, and H. S. Rosenkranz. The mutagenicity
and DNA-modifying effect of haloalkanes. Cancer Res.
3_4: 2576-2579, 1974.
Bunn, William E., Bernard B. Haas, Edward R. Deane, and
Robert D. Kleopfer. Formation of trichloromethanes by
chlorination of surface water. Environ. Lett. 10(3);205-
213, 1975.
Campbell, J. D. Bromide intoxication. South. Med. J.
42:697-673, 1949.
Chemical Economics Handbook (CEH). Menlo Park, Calif.,
Stanford Research Institute. 1975, 1976.
Edwards, K. et al. Studies with alkylating agents. II. A
chemical interpretation through metabolic studies of the
antifertility effects of ethylene dimethane-sulfonate and
ethylene dibromide. Biochem. Pharmacol. 1£:1783, 1970.
Faidysh, E. V., and M. G. Avkhimenko. Effect of the nematocide
nemagon on the reproductive function of an organism. Tr.-
Uzb. Naucho-Issled. Inst. Sanit., Gig. Profzabol. 8^42-43,
1974. (Abstract)
Fried, Frederick E., and Parviz Malek-Ahmadi. Bromism:
Recent perspectives. South. Med. J. 6£(2):220-222, 1975.
Gleason, M. N., R. E. Gosselin, H. C. Hodge, and R. P.
Smith. Clinical Toxicology of Commerical Products, 3rd ed.
Baltimore, The Williams and Wilkins Co. 1969.
Gordon, C. C. Report on coniferous vegetation collected in
Union County and Magnolia area, Arkansas. Unpublished
report, July 1976.
Neiswander, A. C. Bromide poisoning. J. Am. Inst. Homeopathy
51:104-105, 1958.
Olson, W. A. et al. Induction of stomach cancer in rats and
mice with halogenated aliphatic fumigants. J. Natl. Cancer
Inst. 5_1(6) :1993-1995, 1973.
57
-------
Opitz, J. M., F. R. Grosse, and B. Haneberg. Congenital
effect of bromism. Lancet U7741):91-92, 1972.
Sax, N. Irving. Dangerous Properties of Industrial Materials,
3rd ed. New York, Van Nostrand Reinhold Co. 1968.
Shapovalov, Y. D. Effect of elemental bromine and its
compounds on the organism of workers. Vrach. Pelo 12:110-
115, 1974. (Abstract)
Skopintsev, B. A. Average residence times of some elements
in Black Sea water. Okeanologiya 13_(6) :1015-1019, 1973.
(Abstract)
Stenger, V. A. Bromine. In Kirk-Othmer Encyclopedia of
Chemical Technology, 2nd ed., vol. 3. 1964. p. 750-766.
Tiffany, Mary A., John W. Winchester, and Ronald H. Loucks.
Natural and pollution sources of iodine, bromine and chlorine
1329, 1969.
Vogel, E., and J. L. R. Chandler. Mutagenicity testing of
cyclamate and some pesticides in Drosophila melanogaster.
Experimentia 3£: 621-623, 1974.
Wolfsy, Steven C., Michael B. McElroy, and Yuk Ling Yung.
The chemistry of atmospheric bromine. Geophys. Res. Lett.
2_(6) :215-218, 1975.
Woodbury, D. M. Antiepileptic drugs: Bromides. In_ Antiepileptic
Drugs. 1972. pp. 519-527.
58
-------
CHEMICAL HAZARD INFORMATION PROFILE
Carbon Black
Date of report: August 1, 1976
This chemical was chosen for study because of its high
production volume and its potential for adsorbing carcinogenic
substances.
It is recommended that OTS update its literature search
on carbon black, since this report was written some time
ago. Carbon black is recommended for testing consideration
because of the potential for widespread exposure to the PNAs
present in carbon black.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Carbon black, the darkest and most finely divided
substance known to man, is produced in large quantities and
is used primarily as a reinforcing agent in the manufacture
of rubber tires. While there appears to be no significant
direct toxic effect of carbon black itself, there is a
question of a hazard due to carcinogenic polycyclic aromatic
hydrocarbons known to be adsorbed on some types of carbon
black. The bioavailability of these adsorbed carcinogens
under conditions of human exposure has not yet been adequately
demonstrated, and therefore the human health hazard of
carbon black is equivocal. Pollution from the production of
carbon black is minimal, but through tire wear and disposal
of old tires, carbon black can reach the general environment.
Carbon black is elemental carbon in particulate form.
The individual carbon atoms are arranged in platelets measuring
12 x 24 angstroms (A), similar to graphite, but with the
platelets stacked only roughly parallel to one another.
There are four basic types of carbon black, generally classified
59
-------
according to the production processes used for their manufacture.
The four major processes for carbon black production are the
furnace (either oil or gas) process, the thermal process,
the channel process, and the lamp process. Acetylene black
is a special type of thermal black utilizing acetylene as
the make gas.
The properties of carbon blacks are a function of the
process used to make the material. Table 1 presents the
ranges of properties for different kinds of carbon blacks.
Distinctions between types of various carbon blacks are
based on particle size, surface area, chemical composition
of the surface, and the extent of particle-to-particle
association.
Under an electron microscope, all types of carbon
blacks appear to be spherical particles that are more or
less associated into loose chains. This tendency to form
chains is known as chain structure, or simply structure, and
has been correlated to compressibility and oil absorption.
Structure has an important effect on the properties that
carbon blacks give to rubber formulations, affecting ease of
extrusion, electrical conductivity, and elastic modulus.
Generally, channel and thermal blacks are low in structure,
lampblacks are high, and furnace blacks exhibit a wide
range, depending on production procedures.
Channel carbon black particles range from 100-400 A,
thermal blacks from 1,400 to over 4,000 A, lampblacks from
600-4,000 A, and the versatile furnace blacks from 180-800
A. Surface area values, expressed in m /g of black, are
usually determined in one of two ways. One method of calculation
is by measurement of average particle diameter; however,
errors are introduced into this method through decreases in
surface area in aggregated particles. A more convenient
method is determining N2 adsorption at -193 C, where the
quantity of N2 corresponding to monolayer coverage can be
graphically determined. This method gives external and
internal surface area, and in porous blacks values two or
three times those obtained through calculations from measured
diameters may result. Highly porous blacks are those with a
more irregularly arranged crystalline structure.
When first collected, the bulk density of carbon black
is about 3-lO^lb/ft . Removal of occluded air raises this
to 6-15 Ib/ft . When pelletized for shipping, the bulk
density of carbon black ranges from 20-30 Ib/ft . More
precise values for specific density, obtained through helium
displacement methods, give values of about 1.86 g/cm .
60
-------
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Carbon black is 90-99% pure carbon. Oxygen and hydrogen
are present primarily as complexes with surface carbon
resulting from interactions after the black has been formed.
The carbon content of carbon blacks varies (% by weight)
from 88.4 for high-color channel to 99.5 for thermal acetylene.
The oxygen content varies inversely, with 11.2 for high-
color channel to no measurable amount for thermal acetylene.
Also, the volatile content varies inversely with 18 for
high-color channel and 0.06 for thermal acetylene (Kirk-
Othmer, 1964). Some such complexes are hydroxyl, carbonyl,
and carbonic acid groups, some aromatic hydrogen, lactones,
and heterocyclic ethers. Many carbon blacks adsorb polycyclic
aromatic hydrocarbons (PAHs) during production; PAHs that
have been identified include benzopyrene, naphthalene,
acenaphthylene, phenanthrene, fluoranthrene, pyrene, cyclopenta-
pyrene, phenalenone, benzperylene, anthanthrene, and coronene.
PAHs comprise what is often referred to as the benzene
extractable content of carbon black. Other contaminants
include 0.01-0.2% sulfur from that present in the raw material
and a few tenths of a percent of ash from the water used to
quench the hot black in manufacture. The volatile content
of carbon black is the percent weight loss after heating to
927°C. This is mostly carbon monoxide or carbon dioxide,
and is generally between 1 and 2%, though in some channel
blacks this may be up to 18%. The chemical properties and
reactions of carbon black resemble those of polynuclear
aromatic compounds, and most blacks exhibit a typical aromatic
basicity, with normal pH values ranging from 8-10. A high
proportion of surface oxygen groups tends to lower the pH,
correlating nicely with an increased volatile content.
Production and Use
All types of carbon blacks are produced by thermal decom-
position of hydrocarbons, either through partial burning or by
straight heating. High temperatures that promote uniform
conditions for rapid heat transfer, rapid production of par-
ticles, proper dilution of starting material, and protection
from oxidation are necessary for production of small and uni-
form particle size. Lampblack is produced by burning petroleum
oils and coal tar by-products in shallow open pans with a
restricted air supply. In the channel process, natural gas is
burned in many small fan-shaped flames just below continuously
moving channel irons. Insufficient air for complete combustion
is provided, and carbon black forms in the flame and is deposited
by impingement on the channel. Stationary scraper blades remove
the black from the channels. About 5% of the carbon in the gas
is recovered as black, but new techniques of enriching the gas
with oil are being used because of the rising price of natural
gas.
62
-------
Thermal blacks are produced by the thermal decomposition of
natural gas in the absence of air. Unlike all the other methods
of carbon black production, the thermal process is cyclic rather
than continuous in operation. The generator, which is a large
furnace filled with a checker-work of silica brick, is heated to
2,400-2,800°C by complete combustion of natural gas and air.
When the desired temperature is obtained, the air is cut off and
natural gas is admitted for the decomposition stage. The heat
from the brickwork cracks the gas to elemental carbon and hydro-
gen gas. When the brick is too cool for further cracking, the
gas is cut off and the carbon smoke is flushed from the genera-
tors. The cycle then repeats, with reheating of the checkerbrick
by combustion of gas and the hydrogen produced in the decomposi-
tion cycle. About 40-50% of the carbon in the fuel is recovered.
The particle size can be controlled somewhat by diluting the
natural gas with recirculated resultant gas, which allows smaller
carbon particles to form in the more dilute atmosphere.
The furnace process, which now dominates the carbon black
industry, is similar to the channel and lamp processes in that it
also involves incomplete combustion of hydrocarbons, but in the
furnace process this takes place in a large furnace with a single
flame utilizing large volumes of hydrocarbons and air. In the
gas furnace process, air and natural gas are mixed and ignited in
the ratios required for properly incomplete combustion. Adjust-
ment of air/gas ratio, flow, and turbulence allows the character-
istics and yield of the black to be regulated. For larger size
gas furnace blacks, the yield may be between 25 and 30%, while
the production of small particles recovers only about 10-15% of
the total carbon. In the oil furnace process, air and natural
gas'are burned completely in a process separate from the decompo-
sition step. The oil, typically a highly aromatized petroleum
oil, is atomized and injected into the heat of the swirling zone
of complete combustion, where it is decomposed to a fine carbon
smoke and hydrogen gas. Here again, the qualities of the black
can be adjusted, but over a very wide range in this case, by
changing ratios in the oil/air/gas mixture and in furnace and
injector design. Yields in this process are high, typically
around 55%, and will vary between 35 and 65%.
After the thermal decomposition step has taken place, the
bl*ck must be collected and packaged for further use. In the
lamp process, most of the black is collected through precipita-
tion in large settling chambers. Channel black is primarily
collected directly by scraping from the channels themselves.
Neither of these measures is completely efficient, and collecting
devices such as cyclones, precipitators, and filters are employed
to varying degrees. The off-gas from the thermal and furnace
processes, which contains the suspended carbon black particles,
must first be cooled to about 500°C in a spray tower. Following
this step, collection devices such as electrostatic precipitators,
63
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wet scrubbers, cyclones, and bag filters are used to collect the
black. In older plants, electrostatic precipitators and cyclones
were widely utilized, but due to economic and versatility prob-
lems with precipitators as well as greatly improved designs for
bag filters, the presently preferred set-up for collection systems
consists of an agglomerating device or cyclone followed by bag
filters. This sequence of collectors will remove over 99% of the
carbon black from the combustion gases.
The recent trends in carbon black production have been to
shift emphasis away from channel black, which historically played
a large role, to furnace black due to advances in furnace tech-
nology which allow a wide range of blacks with properties similar
to channel blacks to be produced. Furnace black now makes up
almost 92% of U.S. production, thermal black about 8%, with
channel and lampblack together comprising less than 0.1% of the
total output.
Production data for carbon blacks are shown in Tables 3 and 4,
Carbon black consumption data are shown in Table 5. About
93% of the carbon black produced in the United States is consumed
by the rubber industry; of this, 90% is used as a reinforcing
agent in rubber tires. About 6-7 Ib of carbon black goes into
each tire, the primary effect of which is to extend the abrasion
resistance and thus the useful life of the tire. The type of
carbon black used and the amount added also affect the electrical
conductance, heat buildup, resilience, flex resistance, and
processing characteristics of the rubber. Besides tire treads,
carbon black is also added to rubber belts, hoses, wire insula-
tion, flooring, motor mounts, and rubber gaskets. All kinds of
carbon black are \itilized for these applications, depending on
the specific characteristics required.
The second largest consumer of carbon black is the ink
industry, especially for use in newsprint. Furnace black has
largely replaced channel black for this application. Channel and
furnace blacks are also used in book, letterpress, lithographic,
gravure, carbon paper, and typewriter ribbon inks. Other pigment
applications for various grades of carbon black include uses in
paints, lacquers, enamels, coloring plastics, black paper, nylon
and other fibers, tinting dispersions, and as a toner in electro-
static copying machines.
Other useful applications of carbon black are as an anti-
static agent in phonograph records, to prevent photo and thermal
oxidation in polyolefins, in black tape for wrapping high-voltage
transmission cables, in dry-cell batteries (acetylene black), for
high-temperature insulation, and in carbon electrodes (lampblack).
64
-------
Table 3.
Year
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
Carbon Black
Furnace
1,612
1,567
1,677
1,686
1,821
1,933
2,142
2,028
2,364
2,505
2,506
2,629
2,930
3,170
3,116
Production
Thermal
149
145
172
194
232
272
276
306
305
326
312
342
249
316
274
by Process
Channel
292
262
207
179
170
148
153
149
143
132
114
46
22
14
^ ^
(millions of Ibs)
Total
2,054
1,980
2,056
2,059
2,223
2,354
2,572
2,484
2,812
2,963
2,931
3,017
3,201
3,500
3,390
Source: SRI, 1976
Table 4. Carbon Black Production by Raw Materials (millions of Ibs)
Year
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
From natural gas
638
598
537
543
574
593
524
466
455
456
381
322
271
246
From liquid hydrocarbons
1,415
1,381
1,520
1,516
1,649
1,761
2,048
2,018
2,357
2,507
2,550
2,695
2,930
3,254
3,207
Source
65
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Table 5. Carbon Black Consumption by End Use (millions of Ibs)
Year
Elastomers
Printing inks
Paint
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
Source:
1,363
1,383
1,551
1,630
1,789
1,946
2,131
2,072
2,446
2,616
2,486
2,678
2,954
3,115
2,925
SRI, 1976.
48
43
41
46
46
54
64
64
68
73
73
75
82
84
83
12
15
16
13
18
11
12
13
13
18
15
19
21
22
19
The Food and Drug Administration (FDA) has lifted its con-
ditional approval of channel black for use as a food color additive
for licorice and jellybeans. This was done because the industry
could not meet the conditions of approval, which were requirements
for specifications to differentiate channel from other types of
black and for analytical methods to detect PAHs in channel black
at a level of 2 ppb. The only other black approved for food-
associated use by the FDA is furnace black, which may be incor-
porated at less than 10 ppb into rubber articles for repeated use
in food preparation.
Health Aspects
Much of the original toxicity testing of carbon black was
carried out by Carl Nau, Jack Neal, and Vernie Stembridge in the
late 1950's, and their work is still the most complete body of
information on carbon black available. Their work, like most of
the available literature, concentrates on the carcinogenic poly-
cyclic aromatic hydrocarbons, especially benz(a)pyrene, that are
known to be adsorbed on several types of black. Channel blacks
are low in this benzene extractable content, thermal and lamp-
blacks are high, and furnace blacks fall into an intermediate
category. Blacks with average diameters under 300 A usually
contain no PAHs, while those over 500 A contain a variety (Steiner,
1954).
66
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Male mice fed a diet containing 10% furnace black for 72
weeks showed no gross changes from controls, while alive or when
autopsied, whereas animals given the benzene extract of this
black incorporated into the diet developed a significant number
of tumors in the gastrointestinal tract (Nau et al., 1958). In
another study, various air pollutant particulates including
carbon blacks were incorporated into the diet of 83 mice, of
which 8 developed gastric tumors (Neal and Rigdon, 1969).
Nau and his associates (1958) painted the skins of mice,
rabbits, and monkeys with a 20% suspension of carbon black in
water, cottonseed oil, or mineral oil three times per week for a
year and observed no changes from controls, while the benzene
eluted component of the same black induced skin malignancies in
all three species.
In another set of experiments, 300-mg pellets of carbon
black from which benz(a)pyrene could be eluted were injected
subcutaneously into mice and induced two sarcomas in 50 mice. A
black which did not yield any PAHs on benzene elution was able to
induce one sarcoma in 50 mice when similarly injected, although
the same carbon black with 0.09 mg of benz(a)pyrene added failed
to produce any sarcomas. The benz(a)pyrene-containing carbon
black induced 18 tumors in 50 mice when 300 mg was injected
subcutaneously with tricarprylin, an oily solvent (Steiner,
1954).
Pylev (1970) reintroduced benzopyrene into channel and
thermal blacks from which the absorbed compounds had been "burned
out" by heating at 900°C. These carbon blacks, containing 0.01
mg of benzopyrene per 1.0 mg of black, were given in 60-mg doses
to rats by intratracheal intubation. The channel black thus
administered induced tumors in 40.4% of 52 rats in 16 months, and
the thermal black induced lung tumors in 24% of 50 rats in 10
months.
Nau and his associates (1962) carried out a fairly extensive
series of inhalation studies on carbon black. Mice (for their
lifespan), guinea pigs, and monkeys (up to 13,000 total hours)
were exposed to 1.6 mg/rn^ of various types of furnace blacks for
7 hr per day, 5 days per week. No tumors were induced in any of
the animals studied. In histological studies, carbon black was
found scattered through lung tissue both free-lying and inside
macrophages (scavenger cells). In mice, the black was diffuse
and finely distributed, while monkeys progressively developed
diffusely distributed areas of modularity where the black was
concentrated. The walls of the alveoli tended to be thickened,
and in some animals there was some minimal fibrosis which did not
progress with continued exposure. Carbon black was observed to
infiltrate the pulmonary lymph nodes, and was also present in the
liver, spleen, and kidneys of exposed animals but with no apparent
67
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effect. Inhalation of furnace black did produce an increase in
the heart weight/body weight and lung weight/body weight ratios
in mice. Monkeys inhaling furnace carbon black showed electro-
cardiographic changes indicative of atrial and right ventricular
strain after 2,500 hr of exposure. Inhalation by monkeys of a
thermal black resulted in right and left ventricular and septal
hypertrophy. Tests of pulmonary function in mice exposed to
thermal blacks and monkeys exposed to furnace blacks indicated no
changes in air flow or gas exchange.
The key question in the problem of carbon black carcino-
genicity appears to be the degree to which the adsorbed carcino-
genic PAHs are able to be removed from the carbon black under
conditions of human exposure. Human blood plasma, artificial
gastric juice, or artificial intestinal juice did not elute any
PAHs from channel or furnace blacks after 120.5 hr at 28°C and 60
hr at 37°C with intermittent shaking. Cottonseed oil, aqueous
citric acid (pH 3.85), 3% aqueous acetic acid, 3% aqueous sodium
bicarbonate, 3% aqueous sodium chloride, and whole milk did not
remove any PAHs from carbon blacks incorporated into a commercial
rubber fabrication after 7 days at 138°F (Neal et al., 1962) .
Alveolar and peritoneal macrophages are able in vitro to elute
benzopyrene from carbon blacks to which it has been added (Tomingas
et al., 1971).
One segment of the carbon black industry has been examined
for overall mortality rate and for specific mortality due to
cardiovascular disease and cancer. The overall annual
mortality for carbon black workers was low over the 17.5-
year period (1939-56) examined: 3 deaths per 1,000 among carbon
black workers versus an expected annual mortality of 4.9 per
1,000. Death due to cardiovascular diseases was less than
expectancy, as was death from cancer, at 1.2 rather than 1.46
deaths per 1,000 (Ingalls and Risquez-Iribarren, 1961). This
last statistic was not broken down for types of cancers reported
and may thus be misleading; two of the five cancerous lesions
reported in carbon black workers were melanocarcinomas of the
skin, of a type conceivably traceable to carbon black.
Studies have been made of pulmonary function in workers at a
carbon black plant (type unspecified) exposed to concentrations
of carbon dust in the air averaging less than 10 mg/m . The
parameters of function analyzed were forced vital capacity (FVC)
and forced expiratory volume in 1 sec (FEV^). The average annual
decline in FVC for the carbon black workers was more than four
times that expected for a normal male population, while the
average annual decline in FEV^ was almost three times the pre-
dicted value over the 7 years (1964-71) of the survey. Radio-
logical lung changes consisting of discrete reticular and finely
nodular fibrosis were detected in 6 out of the 35 workers (17.1%)
examined. The average exposure of these 6 was 15.6 years (Valic
et al., 1975).
68
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The results outlined in the above presentation can scarcely
be called conclusive in any direction. It appears that carbon
blacks naturally containing adsorbed PAHs do not produce tumors,
while both positive and negative reports on blacks with added
benz(a)pyrene have been presented. It seems possible that under
conditions where a proper lipid solvent is present, such as on
the skin or in certain pathogenic lungs, the carcinogenic PAHs
adsorbed on carbon black may be eluted and thus become available/-
however, this question cannot be resolved from the available
scientific literature.
Environmental Aspects
The carbon black industry is interesting from the pollution
control aspect in that the objective is to produce large quanti-
ties of dense carbon smoke that would under any other circum-
stances be regarded as highly undesirable by-products. But
because this highly divided particulate matter is the product of
the carbon black industry, careful and generally highly efficient
methods have been developed for complete collection for purely
economic reasons. In the thermal and furnace process plants,
systems of electrostatic precipitators, cyclones, and bag filters
will collect over 99% of the black. The general procedure is to
burn the waste gases from the furnace process after the black has
been removed; the major pollutants after this has been completed
are carbon dioxide and, if a sulfur-containing fuel had been
used, sulfur dioxide. The off-gas from the thermal process is
contained and utilized as a fuel due to its caloric value from
the high content of hydrogen gas. In the channel process, the
carbon is collected by impingement on long-channel irons. Much
of the carbon does not impinge in this way, however, and can
escape to the atmosphere.
Channel plants are notorious for the great volumes of black
smoke which they produce and which can be seen over 30 miles
away. Any attempt to regulate the escape of the gases from the
burning houses would require controlling the ventilation to an
extent where the production processes themselves would be irre-
versibly impaired. Only one channel black plant is in operation
in the United States, built near a natural gas field in remote
western Texas. Therefore, complaints of pollution from this
source seldom arise. Since the channel process has been largely
superseded by new furnace technology and no new channel black
plants have been built in the United States since 1950, this
would not seem to present any major problems for the future.
Sources of carbon black to the atmosphere other than from
production processes mainly arise through maintenance procedures,
leaks in plant conveying systems, or loading and unloading opera-
tions. A plantwide vacuum system and good housekeeping proce-
dures where all spillage is picked up and combusted or recycled
69
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can eliminate most problems from this source. Similar controls
should be instituted where carbon black is handled in further
processing (i.e., rubber plants).
The Effluent Guidelines Division of EPA has recommended
criteria of no discharge of carbon black into wastewater from any
type of carbon black plant. The basis for this decision lies in
the fact that the lamp and channel processes are dry, with no use
of water or entry of carbon black into the water. The thermal
and furnace processes are designated as net water consumers,
namely, at the stcige where water is used to quench the hot black
immediately after production. Any waters contaminated with black
through cleanup or wet scrubbers later in the separation process
could be recycled to the quenching step, and the black contained
therein could be reintroduced into the separation process. The
criterion of no discharge into wastewater seems to be achievable
with little impact on the production cost of carbon black.
Since the bulk of the carbon black produced is utilized as a
reinforcing agent for rubber tires, the ultimate disposal of
carbon black into the environment comes through tire wear.
Carbon black contaminated with rubber is thus lost in substantial
quantities along the roadways, although it appears that most of
these particles settle out within a few feet of the road, ulti-
mately entering the soil or being washed into the waterways.
There are no data on the action of carbon black in ecological
media, but it would be expected to be inert under normal con-
ditions, with little washout of any adsorbed chemicals.
Carbon black has some potential for human exposure. Indi-
viduals encountering the highest levels of carbon black will do
so in an industrial environment, such as the carbon black, tire,
or printing ink industries. However, a wider population may also
be exposed to low levels of carbon black inhaled in minute
quantities as a component of tire dust.
REFERENCES
Allan, D. L. The prevention of atmospheric pollution in the
carbon black industry. Chem. Ind., p. 1320-1324, 1955.
Drogin, I. Carbon black. Air Pollut. Control Assoc. 18 (4);216-
228, 1968.
Environmental Protection Agency. Carbon black manufacturing
point source category. Interim final rule making. Fed. Reg.
£1(97):20496-20504, 1976.
Ingalls, T. H., and R. Risquez-Iribarren. Periodic search for
cancer in the carbon black industry. Arch. Environ. Health
2:429-433, 1961.
70
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Kirk-Othmer Encyclopedia of Chemical Technology. New York,
John Wiley and Sons. 1964.
Kirk-Othmer Encyclopedia of Chemical Technology. New York, John
Wiley and Sons. 1965.
Nau, C. A., J. Neal, and V. Stembridge. Physiological effects of
carbon black. I. Ingestion. AMA Arch. Ind. Health 17;21-28,
1958.
Nau, C. A., J. Neal, and V. Stembridge. Physiological effects of
carbon black. II. Skin contact. AMA Arch. Ind. Health 18:511-
520, 1958.
Nau, C. A., J. Neal, V. Stembridge, and R. N. Cooley. Physio-
logical effects of carbon black. IV. Inhalation. Arch. Environ.
Health £(4):415-431, 1962.
Neal, J., and R. H. Rigdon. Stomach cancer and air pollution:
An experimental study in a petrochemical area. Tex. Rep. Biol.
Med. 2!7_(3) :787-793, 1969.
Neal, J., M. Thornton, and C. A. Nau. Polycyclic hydrocarbon
elution from carbon black or rubber products. Arch. Environ.
Health -4:598-606, 1962.
Pylev, L. N. Induction of experimental lung cancer by chemical
substances. Oncology 2_: 441-446, 1970.
Stanford Research Institute. Chemical Economics Handbook. Menlo
Park, Calif. 1976.
Steiner, P. E. The conditional biological activity of the
carcinogens in carbon blacks, and its elimination. Cancer Res.
L4:103-110, 1954.
Tomingas, R., H. U. Lange, E. G. Beck, N. Manojlovic, and W.
Dehnen. The elution of benzo(a)pyrene adsorbed on particles by
macrophages cultured in vitro. Zentralbl. Bakteriol. Parasi-
tenkd. Infektionskr. Hyg. Erste. Abt. Orig. Reihe B Hyg. Praev.
Med. JL55_(2): 148-158, 1971.
Valic, F., D. Beritic-Stahuljak, and B. Mark. A follow-up study
of functional and radiological lung changes in carbon black
exposure. Int. Arch. Arbeitsmed. 34:51-63, 1975.
71
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CHEMICAL HAZARD INFORMATION PROFILE
Cutting Fluids
Date of report: May 1, 1977
These substances were chosen for study because of the
demonstrated presence of nitrosodiethanolamine, a carcinogen, in
certain synthetic cutting fluids.
No further work by this Office concerning occupational
hazards appears necessary because a NIOSH Criteria Document on
cutting fluids is in progress. It is recommended that this
report be referred to the Office of Solid Waste for consideration
of disposal problems. It appears that inadequate disposal
methods represent the major source of nonoccupational exposure of
cutting fluids.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference
documents. Because of the limitations of such sources, it
necessarily follows that this report may not reflect all
available information on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Category Identity
Cutting fluids are liquids applied to a metal cutting tool
to assist in the machining operation by washing away metal chips
or serving as a coolant or lubricant. Many materials find common
usage as cutting fluids: water solutions or emulsions of
detergents and oils; minerals oils; fatty oils; chlorinated
mineral oils; sulfurized mineral oils; and mixtures of the above
(Condensed Chemical Dictionary, 1971).
The exact composition of commercially used cutting fluids is
difficult to determine because of proprietary considerations and
the common practice of additive incorporation at the place of use
(e.g., the machine shop). Table 1 presents a breakdown of the
most commonly encountered constituents of commercial cutting
fluids.
Health Aspects
Documented health problems associated with cutting fluids
are related to occupational exposure. The nature and scope of
the difficulties arising from environmental exposure to cutting
fluid wastes is not well defined. The composition of those
72
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Table 1. Composition of Commercial Cutting Fluids
(A) Synthetic cutting fluid or chemical coolant
50-90% (1) Water
1-10% (2) Rust inhibitors and detergents
(a) sodium nitrite
(b) di- and' triethanoleamines
(c) potassium or sodium soaps
25-50% (3) Lubricating agents
(a) polyether glycols
(b) alkyl-phenol-ethylene oxide
condensation products
0-1% (4) Bactericides
(a) chlorophenols
(b) organic mercurials
(c) iodine compounds
(d) formaldehyde releasers
(e) quaternary ammonium compounds
(f) hexachlorophene
Note: Synthetic cutting fluids are diluted
(20-150:1) with water prior to use.
(B) Soluble or semisynthetic cutting fluids
60-90% (1) Mineral oils
1-5% (2) Water
5-30% (3) Emulsifiers
(a) sodium and amine soaps
(b) sodium sulfonates, naphthenates,
rosinates
1-20% (4) Coupling agents
(a) alcohols
(b) glycol ethers
(c) glycols
1-10% (5) Rust inhibitors
(a) amines
(b) sodium nitrite
(c) fatty oils
(d) sulfurized fatty oils
0-10% (6) Bactericides
(as above)
Note: Soluble cutting fluids are diluted with
water prior to use.
(C) Insoluble or straight oils
80-100% (1) Mineral oils (including sulfurized
mineral oils)
1-40% (2) Fatty oils (including sulfurized
fatty oils)
0-10% (3) Sulfur (combined and suspended)
0-10% (4) Chlorine
(a) chlorinated paraffins; rarely
chlorinated aromatics
0-1% (5) Phosphorus
(a) organic phosphates and phosphites
Source: Adapted from Gleason et al., 1969.
73
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cutting oil effluents reaching a drinking water source is also
obscure. Large users of cutting fluids, however, are more likely
to have pollution restraints on their effluent than the
relatively small-volume users, who may merely pour their spent
fluids down a drain or onto the ground.
Known Occupational Hazards
The problems associated with occupational exposure are many:
eye irritation, pneumonitis, allergic skin sensitization, and
acne and folliculitis which can lead to keratosis and hyperkera-
tosis, ultimately resulting in malignant dyskeratosis and
squamous cell carcinoma if exposure continues (Seba, 1976).
Finklea (1976) reports that there are over 1,000 domestic
producers and that in excess of 780,000 people are occupationally
exposed to cutting fluids in the United States.
Diethanolnitrosamine
Zingmark and Rappe (1976) first reported the formation of
diethanolnitrosamine in a grinding fluid under simulated gastric
conditions. Development of a chemiluminescent detector sensitive
to the N-nitroso group has greatly increased the capacity for
rapid detection of nitrosamines (although problems with the
method remain). Using this instrument, Fan et al. (1977)
reported concentrations of diethanolnitrosamine in commercial
cutting fluids ranging from 0.02 to 2.99% (eight reported
samples). Concern has arisen that the entry of appreciable
quantities of this nitrosamine into a drinking water source may
create a health problem.
Druckrey et al. (1967) reported that diethanolnitrosamine
was a liver carcinogen in rats. A determination of the acute
toxicity of diethanolnitrosamine showed it to have no lethal
effects despite a large dose (7.5 g/kg). An initial long-term
(feeding?) study established that the compound could induce liver
cancer with an average daily dose of 1 g/kg (total dose, 300
g/kg). This study was repeated at a lower average daily dose
level of 0.6 g/kg until one-half of the previous total dose was
administered (total of 150 g/kg over 240 days). Following the
cessation of treatment, all rats from the initial population of
16 died with liver cancer. Four of the 16 also had kidney
adenomas. (No information was reported as to the fate of any
controls.) The authors concluded that diethanolnitrosamine was
an active carcinogen on the basis of the short induction period
and the subsequent rapid development of tumors. They added,
however, that the required active dose is at least 200 times
greater than that with diethylnitrosamine (one of the most potent
carcinogenic nitrosamines). The replacement of the diethylamine
group with the diethanolamine function apparently weakened the
carcinogenic activity but did not alter the organ specificity.
74
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Other Problems
Several additional components of cutting fluid formulations
have potential for causing problems in the health area. These
have been more or less summarized in the next section.
Environmental Aspects
Methods of Disposal
Many synthetic cutting fluids can be successfully biode-
graded prior to disposal. This is based upon the relative ease
with which long-chain fatty acids can be broken down into shorter
chained fatty acids/ thus reducing the "oily" character of the
spent cutting fluid. Oil-base cutting fluids present a special
problem because of the low allowable concentration of oil in
wastewater. Biological degradation of hydrocarbons proceeds
slowly, and therefore it is a common practice to subject spent
cutting oils to physicochemical separation procedures. A process
such as this attempts to separate the oil and water phases such
that each can be dealt with individually. The aqueous phase
often retains some oil, however, and must undergo additional
treatment prior to disposal. The final disposal method is
incineration of either the separated oil or the untreated cutting
fluid. In the latter case, water is driven off as steam and the
recovered oil is used to fuel the unit. This method solves the
water pollution problem but is somewhat costly and may create an
air problem (Bennett, 1973; Bouveng et al., 1972).
Cutting Oil Components
Metals. Spent cutting fluids may contain significant concentra-
tions of metal salts which can adversely affect the efficiency of
sewage disposal plants. Metallic ions may also cause problems if
they accumulate to levels higher than the environment can tolerate
(Bennett, 1973).
Rust inhibitors. Cutting fluids contain significant amounts of
rust inhibitors such as sodium, potassium, or lithium nitrites in
their formulations. At low environmental concentrations, nitrites
can be used as an energy source by microorganisms, while high
levels can reduce the activity of sewage bacteria (Bennett, 1973) .
Phosphates. Some metalworking fluids contain high concentrations
of phosphates which are implicated in excessive algal growth and
eutrophication problems (Bennett, 1973).
Others. Both hydraulic fluids and cutting fluids may contain
polychlorinated biphenyls (PCBs), though their use is currently
being phased out. Boron compounds are being included in some
cutting fluid formulations at a time when the boron levels in
75
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rivers are increasing. Boron is difficult to remove by conven-
tional waste treatment methods, and at high concentrations (over
1,000 ppm) it can interfere with the efficiency of disposal
plants. Some newly developed, more exotic cutting fluids contain
fluorides, iodides, and cadmium salts. These, however, are
apparently rather low-volume products at this time.
An additional difficulty is the presence of biocides in
cutting oil formulations. While the biocide concentrations are
low (initially and especially after dilution), the tremendous
volume of spent cutting fluids generated domestically can add a
sizable environmental burden, especially in localized heavy-use
areas. Another aspect is the apparently common practice of
adding additional amounts of biocides to cutting fluid products
at user sites to "ensure" effective microbial control (Bennett,
1973) .
Nitrosamines
Diethanolnitrosamine has been identified as a contaminant of
several commercial cutting fluids. Fan et al. (1977) reported
diethanolnitrosamine concentrations as high as 2.99% in an undi-
luted, commercially available virgin cutting fluid. The authors
predicted that most cutting fluids containing di- or triethanol-
amines and nitrites as additives would also be contaminated with
this nitrosamine. Health or environmental problems could arise
following the disposition of nitrosamine-containing cutting
fluids in a drinking water supply. None of the noted disposal
methods (with the possible exception of incineration) are known
to remove or reduce this potential problem with any certainty.
Druckrey et al. (1967) reported that diethanolnitrosamine is
very soluble and quite stable in water under laboratory condi-
tions (no indication as to the presence or absence of light). In
natural waters, diethanolnitrosamine may undergo photolytic
decomposition; however, there are no studies to indicate the
half-life of diethanolnitrosamine under such conditions. Never-
theless, photolytic decomposition is effective only at the
surface of waters, and if the nitrosamine is evenly dispersed
throughout a reservoir, only a fraction would reside at the
air/water interface.
It remains to be demonstrated that nitrosamines are present
in user effluent and that the levels found in water subsequent to
dilution are high enough to present a problem.
REFERENCES
Bennett, E. 0. The disposal of metal cutting fluids. Lubr. Eng.
29:300-307, 1973.
76
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Bouveng, H. 0. et al. Handling of spent oil-based products in
the mechanical engineering industry. Pure Appl. Chem. 29(1-
3):201-217, 1972.
Condensed Chemical Dictionary, 8th ed. New York, Van Nostrand
Reinhold Co. 1971.
Druckrey, H. et al. Organotrophic carcinogenic effects of 65
different N-nitroso compounds on BD-rats. Krebsforsch. 69:103-
201, 1967. (Translated by G. Semeniuk and C. Auer, EPA)
Fan, T. Y. et al. N-nitrosodiethanolamine in synthetic cutting
fluids: A part-per-hundred impurity. Science 196;70-71, 1977.
Finklea, John F. Current Intelligence Bulletin: Nitrosamines in
Cutting Fluids. October 6, 1976.
Gleason et al. Clinical Toxicology of Commercial Products, 3rd
ed., Baltimore: The Williams and Wilkins Co., 1969.
Hart, Andrew W. Alkanolamines. In Kirk-Othmer Encyclopedia of
Chemical Technology, 2nd ed., vol. I. 1963. p. 809-824.
Seba, Douglas B. Letter, April 20, 1976.
Zingmark, P. A., and C. Rappe. On the formation of N-nitroso-
diethanolamine from a grinding fluid under simulated gastric
conditions. Ambio 5^:80, 1976.
ADDENDUM
Chemical Week (1977) reported that diethanolnitrosamine has
been identified by David Fine as a contaminant in several popular
consumer products (shampoos, cosmetics, hand and body lotions).
Lijinsky et al. (1972) demonstrated that triethanolamine is
readily nitrosated when treated with sodium nitrite under acidic
conditions. There is some likelihood that the problem of di-
ethanolnitrosamine contamination may be common to other products.
During the course of this project, several additional, more
wide-ranging questions came into view. Perhaps the most signifi-
cant are the health and environmental consequences of the large-
volume use and release of nitrates and nitrites. There is a mul-
titude of problems associated with these materials aside from the
possible nitrosamine implications.
References
Chemical Week, March 30, 1977, p. 29.
Lijinsky, W. et al. J. Natl. Cancer Inst. 49:1239, 1972.
77
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CHEMICAL HAZARD INFORMATION PROFILE
Cyclohexylamine
Date of report: October 21, 1977
This chemical was chosen for study because of reports of its
toxicity in the scientific literature.
Since many other chemicals, especially other aliphatic
amines, are also used as corrosion inhibitors and would therefore
have similar exposure patterns, it is recommended that a con-
tractor review the entire class of volatile corrosion inhibitors.
This contractor report would serve as the basis for a Phase I
document. The carcinogenic potential of these chemicals is the
major impetus for further assessment.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily
follows that this report may not reflect all available informa-
tion on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Chemical Identity
Cyclohexylamine is a colorless liquid at room temperature
and has an unpleasant fishy odor. It has a boiling point of
134.5°C and is a strong organic base (pKb = 3.3). Cyclohexyl-
amine forms an azeotrope with water (boiling point, 96.4°C) and
is miscible with most organic solvents (Condensed Chemical
Dictionary, 1977).
Production and Use
The three processes used in the manufacture of cyclohexyl-
amine (CHA) are the catalytic hydrogenation of aniline, ammonol-
ysis of cyclohexyl chloride or cyclohexanol, and the reduction of
nitrocyclohexane (Shreve, 1967). The first reaction is apparently
the most common and involves the hydrogenation of aniline in the
liquid phase at 135-137°C and 50-500 atmospheres of pressure in
the presence of a catalyst. The CHA yield is approximately 80%
78
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(Kouris and Northcott, 1967). The other reaction products are
unchanged aniline and a high-boiling residue containing cyclo-
hexylaniline and dicyclohexylamine (Merck Index, 1968).
CHA is a reactive primary amine and serves as an intermedi-
ate for a variety of derivatives. These compounds find use in
numerous industries including chemical, paper, rubber, plastic,
textile, pharmaceutical, dye, pesticide, and petroleum. Cyclo-
hexylamine can be added to boiler water and at concentrations of
5 ppm will prevent corrosion and scaling by maintaining suffi-
cient alkalinity to protect surfaces against carbonic acid.
Because CHA forms an azeotrope with water, the chemical enters
the steam phase (vapor-phase corrosion inhibitor), thus pro-
tecting steam lines and vapor equipment as well as the boiler.
Many derivatives of CHA are also used as ferrous corrosion
inhibitors (see Appendixes A, B, and D). The rubber industry
uses CHA mixed with other chemicals to retard the degradation and
discoloration of certain rubber mixtures. Various salts of
cyclohexylamine have long been used as vulcanization accelerators
(Condensed Chemical Dictionary, 1977; CEH, 1975; Holderried,
1967; Shreve, 1967).
Cyclohexylamine formerly found a good market in the produc-
tion of sodium and calcium cyclamates, which were used as arti-
ficial sweeteners. However, the FDA prohibited the use of
cyclamates for this purpose in 1969 (CEH, 1975; Holderried,
1967).
Annual sales figures, as reported by the U.S. International
Trade Commission, are as follows: 1971, 4.8 million Ib; 1972,
4.2 million Ib; 1975, 4.2 million Ib. Figures are not available
for 1973 and 1974. The producers of CHA are listed in Table 1.
Table 1. Domestic Producers and Suppliers of Cyclohexylamine
Producer /location
Abbott Labsa'b
Wichita, Kan.
Monsanto Co.a'b
Sauget, 111. .
Virginia Chemicals, Inc. '
Portsmouth, Va.
Suppliers
BASF Wyandotte, Inc.
Betz
Pennwalt Corp.
Total
Capacity
(10b Ib)
10
2
8
Not reported
Not reported
Not reported
20
, Directory of Chemical Producers (1975)
cChemical Week 1977 Buyers Guide (1976)
Cyclohexylamine and derivatives.
79
-------
Health Aspects
Human
Cyclohexylamine is caustic to skin and mucous membranes, and
its systemic effects in man include nausea, vomiting, anxiety,
restlessness, and drowsiness (Gleason et al., 1969) . Cyclohexyl-
amine may also be a skin sensitizer (Mallette and von Haam,
1952) .
In a human volunteer study of CHA, Eichelbaum et al. (1974)
found a significant increase in the urinary excretion of cate-
cholamines following the oral administration of 10 mg/kg of CHA.
These findings were consistent with others noting the indirectly
acting sympathomimetic effects of Cyclohexylamine.
The Food and Drug Administration banned the use of cycla-
mates as artificial sweeteners in 1969 because of their metabolic
conversion to Cyclohexylamine, which was found to be carcinogenic
in rats (Price et al., 1970). There is no evidence that CHA is a
human carcinogen.
Laboratory Animal
Mutagenicity. Cyclohexylamine appears to have potential for
chromosome damage. However, the results of studies (both j.n
vitro and in vivo) conducted over the last several years have
been contradictory. Several of the studies are summarized below.
In vitro studies. Cyclohexylamine caused a significant
increase in chromosome breaks in cultures of human and Chinese .
hamster fibroblasts (Bladon and Turner, 1971; Dixon, 1973), in a
rat kangaroo cell line (Green et al., 1970), arid in human lympho-
cyte cultures (Stoltz et al., 1970). On the other hand, Brewen
et al. (1971) did not observe a significant increase in chromo-
some aberrations (chromatid breaks) in human lymphocyte cultures,
while Schoeller (1971), who noted no significant increase in the
frequency of chromosome breaks, observed a considerable increase
in chromatid breaks and gaps using a human lymphocyte culture.
In vivo studies. No mutagenic activity was seen in the
host-mediated assay by Brewen et al. (1971) or Voogd et al.
(1973). The dominant lethal test indicated no mutagenic activity
attributable to Cyclohexylamine in rats or mice (Bailey et al.,
1972; Cattanach and Pollard, 1971; Lorke and Machemer, 1974).
CHA failed to induce sex-linked recessive lethals in Dro-
sophila (Knaap et al., 1973).
Other studies failed to demonstrate an increase in the
relative frequency of chromosome aberrations in rat, mouse, or
80
-------
Chinese hamster spermatogonia (Bailey et al., 1972; Cattanach ana
Pollard, 1971; Machemer and Lorke, 1976). In support, Dick et
al. (1974) found no chromosome-damaging effects caused by CHA in
rats or in a group of four human subjects.
Other studies, however, directly contradict these findings
with demonstrations of chromosome damage following in vivo
administration of CHA. Legator et al. (1969) noted a significant
increase in chromosome breaks in the spermatogonia and bone
marrow cells of rats; Petersen et al. (1972) found a significant
increase in dominant lethal effects in mice; Turner and Hutchin-
son (1974) indicated an increase in chromosome abnormalities in
peripheral lymphocytes of fetal lambs; van Went-de Vries et al.
(1975) found chromosome-damaging effects in Chinese hamsters
following oral treatment with CHA.
No clear-cut conclusions as to the mutagenic potential of
cyclohexylamine can be reached because of the many conflicting
studies. Nevertheless, the van Went-de Vries et al. (1975) study
appears the strongest because the purity of their CHA samples was
checked by mass spectrometry and the compound, which is easily
oxidized, was handled at a low pH (2.2-2.4) and in a nitrogen
atmosphere. All other studies reporting the pH of the CHA sample
used values between 7.0 and 7.3, which are not optimal conditions.
It appears likely that much of the lack of agreement among the
published results is attributable to the use of impure CHA (van
Went-de Vries et al., 1975).
Carcinogenicity. A 10:1 mixture of sodium cyclamate and sodium
saccharin(C/S) was added to the diet of rats in concentrations
providing a daily intake of 0, 500, 1,120, or 2,500 mg/kg/day.
Many of the rats were found to convert cyclamate to cyclohexyl-
amine. In the 79th week, one-half of the animals in each group
were given supplemental amounts of cyclohexylamine hydrochloride
in the 'diet at 25, 56, or 125 mg/kg/day. Papillary transitional
cell tumors were found in the urinary bladders of 8 of the
initial 80 rats receiving 2,500 mg/kg/day of the C/S mixture. In
all but one instance, the tumors developed in rats that were
found to convert cyclamate to CHA. There were three bladder
tumors in rats that received the CHA supplements and five in
those that did not (Price et al., 1970).
Cyclohexylamine sulfate was fed in the diet to groups of 50
rats at daily doses of 0, 0.15, 1.5, and 15.0 mg/kg. At the end
of the 2 years, CHA-related organ changes were noted only in rats
receiving the highest dosage. A single bladder tumor (transi-
tional cell carcinoma, grade 2) was found in one of the eight
male survivors in the high-dose group. Spontaneous bladder
tumors have never been recorded in control rats at the testing
facility (Industrial Bio-Test Laboratories) and are reported to
be rare (Price et al., 1970).
81
-------
This finding of carcinogenic activity attributable to cyclo-
hexylamine has not been supported by the results of subsequent
investigators: The results of four studies are summarized in
Table 2. These studies are discussed further under "Chronic
Toxicity. "
Fertility and Teratogenic Effects. Cyclohexylamine has been
shown by several investigators to affect male fertility in rats
(Khera and Stoltz, 1970; Khera et al. , 1971; Green et al. , 1972;
Oser et al. , 1976) . These studies demonstrated that males
treated with cyclohexylamine (or its sulfate or hydrochloride
salt) produced smaller litters than untreated males. CHA was not
found to affect the fertility of female rats.
Pregnant female rats were given daily oral doses of CHA
(1.8, 3.6, 18.0, or 36.0 mg/kg/day) for a period of 7 days
corresponding to the 7th through 13th days of gestation. No
significant differences were seen between the treated and control
groups in maintenance of pregnancy, fetal development, resorp-
tion, or malformation rates (Tanaka et al. , 1973) . In a similar
experiment, CHA was orally administered to pregnant mice at 20,
50, or 100 mg/kg/day for 6 days either from day 0 to day 5 or
from day 6 to day 11 of gestation. Cyclohexylamine once again
failed to exhibit any teratogenic effects in any of the groups.
At 100 mg/kg/day, however, CHA significantly decreased the body
weight of living fetuses and was also embryolethal when admin-
istered from day 6 to day 11 of gestation (the level of embryo-
toxicity of CHA was about the same as its subacute toxicity in
the adult female) (Takano and Suzuki, 1971).
Chronic Toxicity. Some results of recent carcinogenesis studies
on CHA have yielded the following values: 150 mg/kg/day for rats
in a two year time period (Oser et al., 1972); 300 in same con-
ditions (Gaunt et al., 1976); and 400 for mice in an 80-week
period (Hardy et al. , 1976) . The conclusion for each study was
negative. Growth retardation at the higher levels was the only
noted effect of cyclohexylamine on the test animals.
Multigeneration (FI through F$) rat studies conducted with
CHA at dosages of 0, 15, 50, 100, or 150 mg/kg/day over a 2-year
period yielded results that were substantially within normal
limits. Nonprogressive growth retardation and a slight reduction
in litter size and weanling weights were the only changes evident
in the highest dosage groups (Bailey et al. , 1972; Oser et al. ,
1976) .
Acute and Subacute Toxicity. Watrous and Schulz (1950) exposed
rabbits, guinea pigs, and rats to CHA vapors for 7 hr/day, 5
days/week, at an average concentration of 150, 800, or 1,200 ppm.
At the highest level, all animals except one rat showed extreme
irritation and died after a single exposure. Fractional mortality
82
-------
occurred after repeated exposures at 800 ppra. At 150 ppm, four
of five rats and two guinea pigs survived 70 hr of exposure;
however, one rabbit died after only 7 hr. The chief effects were
irritation of the respiratory tract and eye irritation with the
development of corneal opacity. No convulsions were observed.
The IP LD5Q of CHA in mice was 619 mg/kg , and the lethal
dose for rats and dogs was estimated at 350 mg/kg IP and 200
mg/kg IV, respectively. Smaller IV doses in the mouse caused
nervous system depression and slight paralysis in the hindlegs
(also exhibited by dogs given 5-50 mg/kg of CHA). In all cases,
death was attributed to respiratory arrest. Cyclohexylamine
caused liberation of histamine in all three animal species as
evidenced by severe scratching. In addition, CHA produced a rise
in blood pressure and increased cardiac contractile force through
release of endogenous catecholamines (Miyata et al., 1969).
*
A 13-week feeding study with CHA at approximately 30, 100,
or 300 mg/kg/day produced growth retardation and reduced testis
weight in rats receiving the two highest dosages. The reduced
testis weight at the highest level was accompanied by histopatho-
logical evidence of reduced spermatogenesis, amounting to com-
plete arrest and loss of the germinal epithelium in 40% of the
rats given 300 mg/kg/day. Despite this development, a limited
reproduction study showed no statistically significant differ-
ences between the offspring of treated and untreated males (Gaunt
et al. , 1974) .
Environmental Aspects
Little or no information was available on the environmental
impact of cyclohexylamine. A study by Jungclaus et al. (1976)
identified CHA in the effluent from a tire-manufacturing plant at
an approximate concentration of 0.01 mg/1 (+30%).
APPENDIX A. Dicyclohexylamine
Dicyclohexylamine
(di-CHA)
Dicyclohexylamine (di-CHA) is a colorless liquid with a
faint amine odor. It has a boiling point of 256°C and is spar-
ingly soluble in water. Dicyclohexylamine is strongly basic (pKb
= 3.3) (Merck Index, 1968; Condensed Chemical Dictionary, 1977).
The literature outlines several schemes for the manufacture
of dicyclohexylamine. The first process involves the hydrogena-
tion of equimolar amounts of cyclohexanone and cyclohexylamine
83
-------
(Merck Index, 1968). A second process uses the hydrogenation of
aniline in the vapor phase in the presence of a nickel catalyst
to produce up to 95% di-CHA (Kouris and Northcott, 1967).
Dicyclohexylamine is a strongly basic secondary amine having
a reactive amine group which readily yields N-substituted deriva-
tives. It is widely used as a chemical intermediate. Dicyclo-
hexylamine salts of fatty acids and sulfuric acid have soap and
detergent properties useful to the printing and textile indus-
tries. Metal complexes of di-CHA are used as catalysts in the
paint, varnish, and ink industries. Several vapor-phase corro-
sion inhibitors are solid di-CHA derivatives. These compounds
are slightly volatile at normal temperatures and are used to
protect packaged or stored ferrous metals from atmospheric cor-
rosion (Holderried, 1967). Dicyclohexylamine is also used for a
number of other purposes: plasticizer; insecticidal formula-
tions; antioxidant in lubricating oils, fuels, and rubber; and
extractant (Condensed Chemical Dictionary, 1977).
No annual production figures are available for dicyclohexyl-
amine. The domestic producers are: Abbott Laboratories, Wichita,
Kans. (Directory of Chemical Producers, 1975; Chemical Week 1977
Buyers Guide, 1976); Virginia Chemicals Inc., Portsmouth, Va.
(Directory of Chemical Producers, 1975); BASF Wyandotte, Inc.;
and Monsanto Co.
Dicyclohexylamine is somewhat more toxic than cyclohexyl-
amine. Poisoning symptoms and death appear earlier in rabbits
injected with 0.5 g/kg di-CHA (as opposed to CHA). Doses of 0.25
g/kg are just sublethal, causing convulsions and reversible
paralysis. Dicyclohexylamine is a skin irritant (Carswell and
Merrill, 1937).
Pliss (1958) conducted a series of animal experiments with
di-CHA. The first involved mice which received daily subcutane-
ous injections of 0.05 ml of a 2.6% oily solution of di-CHA. The
mice often showed transient convulsions following the injection.
Of the original 57 mice, 15 were alive after 12 months. At this
time, several of the mice began developing local tumors. Post-
mortem of several of the mice revealed a high incidence of
degenerative changes in the liver and kidneys. The results of
this study are summarized below.
Species of
animal (no. )
Mice (57)
Rats (50)
Route of
administration
SC injection
Feeding
Duration of
administration
(months)
11-12.5
12
Total
dosage
(mg)
60.1-79.3
8,875
No. of
tumors
4
2
Type of
tumor
Sarcomas
One hepa
and one
sarcoma
84
-------
The second part of Pliss's experiment involved a rat feeding
study. (For 2 months, administration was actually via subcutane-
ous injection of 30 mg. However, local tissue necrosis forced
the change.) The rats were given 0.5 ml of a 5% oily solution of
di-CHA in the food six times a week. Of the 50 original rats, 36
survived for over 12 months, 22 for more than 18 months. Most of
the animals died of pneumonia. Among the remaining rats, one
developed a liver tumor after 21 months and another developed a
sarcoma after 22.5 months. See above for a summary of this
aspect of the experiment.
Pliss concluded that di-CHA was rather weakly carcinogenic,
since relatively few animals developed tumors and the time span
for tumor development was rather long.
APPENDIX B. Dicyclohexylamine Nitrite
Dicyclohexylamine nitrite
(di-CHAN)
Dicyclohexylamine nitrite is a solid nitrite salt having
some degree of volatility at room temperature and higher. It is
used as a vapor-phase corrosion inhibitor whereby it vaporizes
either from the solid state or from solution and offers protec-
tion against atmospheric rusting. Wrapping paper, plastic wraps,
and other materials may be impregnated with di-CHAN to protect
metal parts during packaging and storage (Nathan, 1967; Archer
and Wishnok, 1976).
No production figures are available for di-CHAN; however,
the Directory of Chemical Producers (1975) lists the Olin Corp.,
East Alton, 111., as a producer.
Prolonged exposure to dicyclohexylamine nitrite vapor is
reported to lead to changes in the CNS, erythrocytes, and methe-
moglobinemia and to disturb the functional state of the liver and
kidneys of human workers. The~author recommends a maximum allow-
able concentration of 0.2 mg/m in the workshop (Paustovskaya et
al., 1973).
The LD50 of di-CHAN by gavage was 80 mg/kg in mice and 325
mg/kg in rats (Paustovskaya, 1974).
Pliss (1958) reported that di-CHAN is a carcinogen in mice
and rats. In the mouse study, each animal received a daily SC
injection of 0.1 ml of a 1% aqueous solution of di-CHAN. Tran-
sient convulsions and excitement sometimes accompanied the
85
-------
injections. Tumors remote from the site of injection were found
in 5 of 54 mice. The first rat study involved once-weekly SC
injections of 0., 5 ml of a 2% aqueous solution. Remote tumors
were found in 7 of 50 rats. In the second rat experiment, di-
CHAN was fed daily in the diet, six times a week, as 1 ml of a 3%
aqueous solution. One rat out of a population of 30 developed a
tumor. The results are summarized below.
Species of
animal (no.)
Mice (54)
Rats (56)
Rats (30)
Route of
administration
SC injection
SC injection
Feeding
Duration of
administration
(months)
12-13
11-13
12
Total
dosage
(mg)
51-59
480-1,195
9,180
No. of
tumors
5
7
1
Pliss concluded that di-CHAN was weakly active, although all
tumors developed at different tissue sites remote from the point
of injection.
Marhold et al. (1967) contested Pliss1s (1958) finding of
carcinogenic activity associated with di-CHAN. In a prolonged
feeding experiment, 14.2 mg/kg of di-CHAN was cidded to the diet
of rats 7 days a week for their lifetimes. No tumors were found
in the population of 20 rats. A second study was conducted using
three dogs which were fed 5-10 mg/kg, 5 days a week for life
(dogs were 14 months old at initiation of the experiment). No
tumors were found in any of the dogs. Despite the small number
of animals studied, and notwithstanding Pliss"s results, the
authors concluded that dicyclohexylamine nitrite was not a car-
cinogen (or at best a very weak one, or so the article implies)
based on the dose given and the length of the study.
APPENDIX C. N-Nitrosodicyclohexylaimine
N-nitrosodicyclohexylamine
Any situation in which nitrite ions and a secondary amine
(such as dicyclohexylamine) are in contact under acidic aqueous
conditions has the potential for production of nitrosamines
(Mirvish, 1975) . Nitrosodicyclohexylamine may be a contaminant.
of dicyclohexylamine nitrite and also perhaps of dicyclohexyl-
amine, however, nitrosodicyclohexylamine is not. carcinogenic
(Norred et al., 1975; Nishie et al., 1974). Its lack of car-
cinogenicity may be traceable to the presence of only one hydro-
gen on each carbon alpha to the nitrogen (Lijinsky, 1977).
86
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APPENDIX D. Other Cyclohexylamine Derivatives
Many other salts of cyclohexylamine are used as vapor-phase
corrosion inhibitors. There is very limited information avail-
able on these compounds in Western literature; however, the
Russians have published a number of studies. Refer to Tables D-l
and D-2 for a summary of the acute toxicity associated with
several of these salts.
Table D-l. LDco Values for Cyclohexylamine Derivatives
Substance
CHA-benzoate
CHA-o-nitrobenzoate
CHA-m-nitrobenzoate
CHA-p-nitrobenzoate
CHA-3 , 5-dinitrobenzoate
CHA-carbonate
CHA-chr ornate
Mouse LD
Route (mg/kg)
Gavage
Gavage
Gavage
Gavage
Gavage
Gavage
Gavage
1,400
2,075
490
1,590
025
—
224
Rat LD
(mg/kgj
3,300
--
4,800
1,950
1,600
820
228
Source: Paustovskaya, 1974.
Table D-2. LDCQ Values for Dicyclohexylamine Derivatives
Substance
di-CHA-benzoate
di-CHA-o-nitrobenzoate
di-CHA-m-nitrobenzoate
di-CHA-p-nitrobenzoate
di-CHA-carbonate
Mouse LD
Route (mg/kg)
Gavage
Gavage
Gavage
Gavage
Oral
290
300
364
318
~ ~
Rat LD,-n
(mg/kgr
700
925
1,060
1,620
1,075
Source: Paustovskaya, 1974; Garshenin et al., 1973.
The chromates, benzoates, and nitrobenzoates were also found
toxic following dermal application. One study indicated that the
daily application of 625 mg/kg of CHA-chromate to the shaved skin
of rabbits and rats caused the death of five of seven animals
within 3-10 days, and the daily application of 1,500 mg/kg CHA-
chromate caused the death of all experimental animals within 4
days. Necropsy revealed an enlarged bladder, blood in the urine,
and dystrophy of nerve cells, liver, and kidneys (Paustovskaya
and Rappoport, 1966).
87
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91
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CHEMICAL HAZARD INFORMATION PROFILE
1,6-Diaminohexane
Date of report: June 6, 1978
This chemical was chosen for study because of its
possible presence in consumer products and its potential for
nitrosamine formation.
The following recommendations are made regarding further
OTE evaluation of the possible health or environmental
hazards of 1,6-diaminohexane:
(1) Require TSCA Section 8(a) submission—Better
information is needed on uses so that EPA can
estimate the extent of nonoccupational exposure to
this chemical.
(2) Consider need for testing—Diaminohexane is a
high-volume chemical which has demonstrated toxic
effects at low doses.
(3) Transmit to NIOSH on an FYI basis—NIOSH has
scheduled a criteria document for aliphatic di-
and polyamines.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
1,6-Diaminohexane (hexamethylenediamine) , C,-H^gN2,
is a colorless, combustible solid which melts at>39-42°C.
It is somewhat soluble in water, ethanol, and ether (Hawley,
1971).
Production and Use
Diaminohexane can be manufactured in two ways (Hawley,
1971):
(1) Reaction of adipic acid and ammonia (catalytic
vapor phase) to yield adiponitrile, followed by
liquid-phase catalytic hydrogenation.
92
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(2) Chlorination of butadiene followed by reaction with
sodium cyanide (cuprous chloride catalyst) to 1,4-
dicyanobutylene, and hydrogenation.
The production volume of diaminohexane was 750 million Ib in
1975 (U.S. International Trade Commission, 1977). The 1975
Directory of Chemical Producers lists the following manufacturers
of diaminohexane (SRI, 1976): Celanese Corp., Celanese Chemical
Co. Division, Bay City, Tex.; E. I. du Pont de Nemours & Co.,
Inc., Polymer Intermediates Department, Orange, Tex., and Victoria,
Tex.; El Paso Natural Gas Co., El Paso Products Co., subsidiary,
Odessa, Tex.; Monsanto Co., Monsanto Textiles Co., Pensacola,
Fla.; and R.S.Ai. Corp., Ardsley, N.Y.
Celanese Chemical Co. states that diaminohexane is used as
a raw material for nylon fiber and plastics; in the manufacture
of oil-modified and moisture-area types of urethane coatings; in
the manufacture of polyamides for printing inks, dimer acids,
and textiles; and as an oil and lubricant additive (probably as
a corrosion inhibitor) (McCurdy, 1977). Diaminohexane is also
used in paints and as a curing agent for epoxy resins (Tkachenko,
1976).
Health Aspects
Continuous 90-day inhalation of 1 mg/m of diaminohexane by
albino rats caused an increase in the number of reticulocytes
(only at the beginning of the exposure) and an increase in the Vi
antibody concentration. The animals also exhibited a decrease in
the number of eosinophils, suppressed leukocytic activity,
retarded growth/ and a disturbance of the chronaxy correlation of
the muscle antagonists. Diaminohexane at a concentration of 0.04
mg/m caused similar but less pronounced changes. Diaminohexane
at 0.001 mg/m3 had no effect (Kulakov, 1965).
Exposure of rats to an atmosphere containing 1.25 mg/m
diaminohexane for 4 hr/day for 8 days decreased the threshold of
neuromuscular excitability, increased blood leucocyte and liver
glycogen levels, caused disorders of renal excretory capacity,
and altered the phagocytic activity of neutrophils (Tkachenko,
1976).
Diaminohexane inhibited DNA and RNA formation in vitro in
studies using rat embryo and human amnion cell cultures (Trak-
htenberg et al., 1976).
Intraperitoneal injection of diaminohexane into rats inhib-
ited ovarian ornithine decarboxylase activity which had been
stimulated by human chorionic gonadotropin (Guha and Janne,
93
-------
1977). Diaminohexane injected into mice bearing ascites-car-
cinoma cells powerfully decreased ornithine decarboxylase activ-
ity in the carcinoma cells (Kallio et al., 1977).
An iin vitro study showed that diaminohexarie inhibited
collagen-induced human platelet aggregation (Jobin and Tremblay,
1969).
Occupational exposure to epoxy resins and their hardeners
(including diaminohexane) was studied in 488 workers. Prolonged
contact caused skin damage, allergic rhinitis, bronchial asthma,
impairment of bronchial permeability, toxicoallergic hepatitis,
gastritis, colitis, hypergammaglobulinemia, increased transa-
minase activity, and eosinophilia of the peripheral blood (Gul'ko,
1971) .
Environmental Aspects
The estimated release rate of diaminohexarie to the environ-
ment is 12.8 million Ib/year. Diaminohexane is reactive toward
oxidizing agents (Dorigan et al., 1976).
REFERENCES
Dorigan, J., B. Fuller, and R. Duffy. Scoring of Organic Air
Pollutants. Chemistry, Production, and Toxicity of Selected
Synthetic Organic Chemicals. 1976.*
Guha, S. K., and J. Janne. Inhibition of ornithine decarboxylase
in vivo in rat ovary. Biochem. Biophys. Res. Commun. 7_5(1) : 136-
142, 1977. (As stated in CBAC abstract)
Gul'ko, S. N. Damage to respiratory organs under the occupa-
tional effects of epoxide resins. Klin. Med. 4_9_(12) : 107-109,
1971. (As stated in KEEP abstract)
Hawley, G. G. (ed.). The Condensed Chemical Dictionary, 8th ed.
New York, Van Nostrand Reinhold Co. 1971.
Jobin, F., and F. Tremblay. Platelet reactions and immune pro-
cesses. II. Inhibition of platelet aggregation by complement
inhibitors. Thromb. Diath. Haemorrh. 2_2_(3)-.466-481, 1969. (As
stated in CBAC abstract)
Kallio, A., H. Poso, S. K. Guha, and J. Janne. Polyamines and
their biosynthetic enzymes in Ehrlich ascites-carcinoma cells.
Modification of tumour polyamine pattern by diamines. Biochem.
J. 166 (1):89-94, 1977. (As stated in author abstract)
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of sorie informa-
tion is not possible. The environmental release data were taken
"from the NSF/Rann Research Program on Hazard Priority Ranking of
Manufactured Chemicals.
94
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Kulakov, A. E. The effect of small concentrations of hexamethyl-
enediamine on experimental animals under conditions of chronic
inhalation poisoning. Gig. Sanit. ^£(5):15-20, 1965. (English
translation)
McCurdy, P. P. (ed.). Chemical Week 1978 Buyers Guide. New
York, McGraw-Hill, Inc. 1977.
SRI International. Directory of Chemical Producers. Menlo Park,
Calif., Stanford Research Institute. 1976.
Tkachenko, A. E. Experimental data on the nature of the primary
response of an animal under the effect of hexamethylenediamine.
Gig. Tr. Prof. Zabol. 12_: 51-52, 1976. (As stated in CBAC abstract)
Trakhtenberg, I. M., I. S. Brit, and Y. I. Morgunova. Use of
spectral microanalysis of cell cultures for evaluating the
comparative toxicity of new chemical substances. Gig. Sanit.
3.0^:54-56, 1976. (As stated in CBAC abstract)
U.S. International Trade Commission. Synthetic Organic Chemi-
cals. U.S. Production and Sales, 1975. U.S. ITC Publ. No. 804.
1977.
95
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CHEMICAL HAZARD INFORMATION PROFILE
1,2-Dichloroethane
Date of report: September 1, 1977
This chemical was chosen for study because of its high
production volume.
It is recommended that OTS continue its ongoing hazard
assessment of 1,2-dichloroethane and then proceed to a Phase
I report. The reasons for concern about 1,2-dichloroethane
are its potential carcinogenicity and its high rate of
release into the environment. A requirement for TSCA Section
8(d) submissions is also recommended in order to improve the
base of information for Phase I assessment.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
1,2-Dichloroethane (DCE) is a colorless oily liquid
with a chloroform-like odor. It is stable to water, acids,
and bases, and also resists oxidation. Ethylene dichloride
is miscible with most common solvents but is only slightly
soluble in water. It has a boiling point of 83.5°C. In
1975, DCE was the 16th highest volume chemical produced in
the United States (CCD, 1977).
Production and Use
1,2-Dichloroethane is produced by the vapor- or liquid-
phase reaction of chlorine with ethylene in the presence of
a catalyst. When chlorine is combined with ethylene, both
substitution and addition reactions occur; ethylene dichloride
is the major product only under certain conditions. In a
representative industrial scheme, chlorine (combined with
ethylene dibromide and heated to 50°C) reacts with a stream
of ethylene gas and is passed to a condenser. The ethylene
dibromide liquefies and is recycled. DCE is subsequently
condensed and purified by fractional distillation. The
yield is approximately 96-98%. Metallic chlorides (e.g.,
ferric, aluminum, copper, or antimony) are commonly used'as
the catalyst. Most commercial producers currently use a
ferric chloride catalyst in a liquid-phase process.
96
-------
When considerable excess hydrogen chloride is available, the
oxychlorination of ethylene is the preferred method of DCE
synthesis. This process reacts ethylene, hydrogen chloride, and
air in a fluidized or fixed-bed catalytic process. The catalyst
is copper chloride (SRI, 1975; Bardie, 1967; Lowenheim and Iloran,
1975).
Table 1 lists the major producers of 1,2-dichloroethane in
the United States. The available supply of DCE for the merchant
market is less than the production capacities contained in Table
1 because only the 1,2-dichloroethane produced by the direct
chlorination of ethylene can be isolated and sold. 1,2-Dichloro-
ethane manufactured via the oxychlorination of ethylene is used
captively as an intermediate in vinyl chloride production and
cannot be separated from that production (SRI, 1975). Table 2
offers a compilation of production and sales figures for DCE over
the last several years.
Table 1. DCE Producers, Plant Locations, and Capacities
Capacity as of 12/74
Producers and plant locations (10° Ib)
Allied Chemical Corp. 650
Baton Rouge, La.
American Chemical Corp. 300
Long Beach, Calif.
Conoco Chemicals
Lake Charles, La. 1,000
Diamond Shamrock Chem. Co.
Deer Park, Tex. 260
Dow Chemical U.S.A.
Freeport, Tex./Oyster Creek, Tex. 2,400
Plaquemine, La. 1,160
Ethyl Corp.
Houston, Tex. 260
Baton Rouge, La. 550
B.F. Goodrich Chem. Co.
Calvert City, Ky. 1,000
PPG Industries
Lake Charles, La. 1,000
Guayanilla, P.R. 335
Shell Chem. Co.
Deer Park, Tex. 1,200
Norco, La. 1,165
Union Carbide Corp.
Taft, La. 150
Texas City, Tex. 150
Vulcan Materials Co.
Geismar, La. 240
Total 12,320
Source: SRI, 1975.
97
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Table 2. Production3 and Sales of DCE (10 Ib)
Year
1960b
1965*!
1970
1973c
1974*; ,
1975C'd
Production
1,267
2,850
7,460
9,293
9,165
7,977
Sales
438
309
1,314
1,351
1,314
762
Production totals may be understated because
some EDC is produced but not separated or
accurately measured and, therefore, riot
accurately reported by some producers.
bSRI, 1975
CU.S. International Trade Commission, 1970,
1973, 1974, 1975.
Reasons for the production decline are not
clear; however, the drop-off may only
reflect short-term recessionary influences.
The great majority of all 1,2-dichloroethane produced in the
United States is used as the starting material in the manufacture
of vinyl chloride monomer (VCM). Formerly, DCE, either by itself
or in combination with other solvents, was of considerable
importance as a commercial solvent and extractant. At this time,
however, 1,2-dichloroethane has been replaced in these applica-
tions by methyl chloroform, trichloroethylene, and perchloro-
ethylene, all of which are made from ethylene dichloride. Other
important commercial products derived from ethylene dichloride
include vinylidene chloride and ethyleneamines. Formulations of
tetraethyl lead, the gasoline antiknock additive, incorporate DCE
as a lead scavenger. This application of DCE is expected to
continue to decline because of the phasing out of leaded gaso-
lines. Miscellaneous uses of 1,2-dichloroethane include solvent
applications (e.g., textile cleaning, metal degreasing, and in
some formulations of acrylic-type adhesives), production inter-
mediate for polysulfide elastomers, constituent of nitrile and
polysulfide rubber cements, component of upholstery and carpet
fumigants, and in the manufacture of grain fumigants (SRI, 1975;
Gleason et al., 1969). Additional uses reported in the Condensed
Chemical Dictionary (1977) include: paint, varnish, and finish
removers; soaps and scouring compounds; wetting and penetrating
agents; and ore flotation. See Table 3 for a listing of the
major uses of ethylene dichloride; Table 4 presents a breakdown
of the consumption patterns for 1974 and 1976.
98
-------
Table 3. DCE Consumption Pattern (%)
1974
1976
Vinyl chloride
Methyl chloroform
Trichloroethylene
Perchloroethylene
Vinylidene chloride
Ethyleneamines
Lead scavenger
Miscellaneous
Exports
81
3
3
3
2
3
2
neg.
3
100
86
3
2
2
-
3
2
-
-
100
Adapted from: SRI, 1975; EPA, 1977a.
Domestic consumption of DCE is projected to increase by an
estimated 4% annually through 1979. Currently, over 90% of the
vinyl chloride produced in the United States is based on DCE;
the remainder is manufactured by the addition of hydrogen chlo-
ride to acetylene. The latter process was responsible for 48% of
U.S. vinyl chloride production in 1963 and could be used to
replace the currently favored DCE route (U.S. EPA, 1977a).
Health Aspects
Human
The primary effects of DCE exposure are CNS depression and
gastrointestinal upset. These symptoms are characteristic of
acute, subacute, and chronic exposure to 1,2-dichloroethane.
Liver, kidney, and adrenal injuries occur in a dose-related
fashion. The symptom of nausea and vomiting is quite striking
and is similar to that seen from carbon tetrachloride (Irish,
1963) .
The NIOSH Criteria Document on 1,2-dichloroethane (1976) is
replete with documented cases of fatal and nonfatal human expo-
sure to ethylene dichloride. Most of the injurious exposures
were acute episodes and occurred through either accidental or
industrial exposure. Ingestion of 20 to 50 ml (30-70 g) of DCE
is often fatal within a few days at most (Gleason et al., 1969).
Blood disorders appear characteristic of DCE ingestion, with
clotting difficulties being the most common. Death is often
attributed to circulatory and respiratory failure, with varying
degrees of liver and kidney damage (NIOSH, 1976).
The effects of acute exposure to DCE by skin absorption and
inhalation are similar to those seen following ingestion, although
99
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blood disorders are less prominent. Headache/ weakness, eye
irritation, cyanosis, nausea, and vomiting appear first, followed
by loss of consciousness and respiratory and circulatory failure.
Postmortem findings often include damage to the liver, kidneys,
and lungs (NIOSH, 1976).
Although fatal cases have been reported following chronic
exposure to DCE, fatalities are more commonly associated with
acute episodes. Nonetheless, progressive chronic effects can
result if DCE exposure is not adequately limited. Rosenbaum
(1947) reported that symptoms of acute exposure can rapidly
develop following several exposures to 75-125 ppm of DCE. A
number of Rosenbaum*s cases resulted in death when the worker
experienced acute poisoning symptoms two or more times over a 2-
to 3-week period. Urosova (1953) reported that 1,2-dichloro-
ethane appeared in the milk of nursing mothers who were occupa-
tionally exposed to DCE by inhalation and skin adsorption. In a
related experiment, the author measured the amount of DCE in
breath and milk samples from a woman exposed to approximately
15.5 ppm of 1,2-dichloroethane for an unspecified length of time.
Eighteen hours following the exposure, 0.20-0.63 mg/100 ml 1,2-
dichloroethane was found in her milk and 0.01-0., 02 mg/1 (2-4 ppm)
was found in her breath.
Animal
Animal studies with DCE have demonstrated effects similar to
those reported in humans, including narcosis, pulmonary conges-
tion and edema, blood clotting disorders, and liver, adrenal, and
kidney damage (NIOSH, 1976; Irish, 1963). Heppel et al. (1944)
demonstrated corneal clouding in dogs following DCE exposure;
however, this has not been observed in humans.
EPA was officially notified by NCI on November 14, 1977, of
the preliminary results of a 90-day rat and mouse feeding study.
The preliminary findings were as follows:
Rat—Male: Squamous cell cancer of the forestomach; heman-
giosarcomas at all sites, e.g., liver, spleen. Female:
Mammary adenocarcinoma.
Mouse—Male: Hepatocellular carcinoma? Lung adenoma?
Hepatocellular carcinoma? Lung adenoma? Female: Mammary
adenocarcinoma; lung adenoma? Endometrial polyps?
1,2-Dichloroethane was also studied as part of NCI's biossay
program. DCE was administered by gastric intubation to mice and
rats of both sexes five times per week over a period of 78
weeks. The following dose levels were used:
100
-------
Species Sex Low dose High dose
Rat M&F 50 mg/kg 100 mg/kg
Mouse M 100 200
F 150 300
The study has not been finalized; however, the preliminary
results described below appear to indicate that DCE is carcino-
genic in both species.
Male rats developed statistically significant numbers of
squamous cell carcinomas of the forestomach (a rare growth in the
rat species tested) as well as statistically significant numbers
of hemangiosarcomas of the circulatory system. Female mice and
rats, on the other hand, developed statistically significant
numbers of mammary gland adenocarcinomas. The tentative conclu-
sion of the bioassay report is that DCE is a carcinogen in male
and female rats and female mice (Dr. Sidney Siegel of NCI,
meeting presentation, December 15, 1977).
The tumors observed in the DCE experiment are similar to
those seen by Olson et al. (1973) in their gastric intubation
study of ethylene dibromide (EDB), the brominated analog of DCE.
However, the growths observed in the DCE study were not as
dramatic as those associated with EDB in terms of both the
numbers of tumors observed and the rapidity of their development
(Dr. Ciprieno Cueto of NCI, personal communication, November 3,
1977; Dr. Sidney Siegel of NCI, meeting presentation, December
15, 1977).
1,2-Dichloroethane has been shown to be weakly mutagenic in
bacteria without metabolic activation (Voogd et al., 1972; Voogd,
1973; Brem et al., 1974; Rosenkranz et al., 1974). Attempts to
increase the bacterial mutagenic activity of DCE using a rat
liver homogenate for activation (Ames test) were unsuccessful.
The authors ascribed the difficulty to metabolic inefficiencies
in the in vitro system (McCann et al., 1975). The major metab-
olic products of DCE in mammalian systems have been tentatively
identified as chloroacetic acid, chloroethanol, and chloroacet-
aldehyde (Yllner, 1971; Heppel and Porterfield, 1948). In the
Ames test, chloroacetic acid was negative while chloroethanol
responded weakly, in similar fashion to DCE. Chloroacetaldehyde,
however, was hundreds of times more effective than DCE or chloro-
ethanol (on a molar basis) in reversion of Salmonella bacterial
strains (McCann et al., 1975).
Chloroacetaldehyde and chloroethylene oxide have been
implicated as likely in vitro metabolites of vinyl chloride
(Gothe et al., 1974). Chloroethylene oxide is known to rearrange
101
-------
spontaneously to chloroacetaldehyde (Zief and Schramm, 1964).
Furthermore, both compounds have been found mutagenic in the Ames
test (McCann et al., 1975; Malaveille et al., 1975), suggesting
that one or both of these metabolites may be the true active
carcinogenic form of vinyl chloride (McCann et al., 1975). If
the preceding is verified and chloroacetaldehyde is found to be
the active metabolite of both DCE and vinyl chloride, the impli-
cations for DCE would obviously be of great significance. McCann
et al. (1975) reported that chloroacetaldehyde, on the basis of
its potent mutagenic activity, is likely to be a carcinogen and
should be evaluated for its carcinogenic potential. Lawrence et
al. (1972), in an extensive study of chloroacetaldehyde, observed
lung changes in exposed rats that are suggestive of a premalig-
nant condition.
In mutagenic studies, 1,2-dichloroethane displays greater
killing and mutagenic effectiveness than monofunctional agents
(such as methyl methanesulfonate). This phenomenon (shared by
neutrons and bifunctional alkylating agents, among others) has
been described as "genetic death" and is characterized by the
ability to cause considerable damage to DNA and equal damage to
proteins (as measured by enzyme inactivation). As an example,
consider ethylene oxide and diepoxybutane: while both exhibit
the same approximate immediate toxicity, the bifunctional agent
provokes a delayed killing response that renders diepoxybutane
two orders of magnitude more toxic at the stage of maturity of
barley plants (in this instance). This difference can be
explained in terms of the severe consequences of the cross-
linking of DNA, especially with respect to the inability of
exposed cells to duplicate DNA and perform mitosis. Furthermore,
cross-linking may follow primary alkylation at a site which is
not, per se, considered to be involved in mutagenesis, and thus
the effect of the bifunctional agent is considerably enhanced
over that seen for monofunctional chemicals (Ehrenberg et al.,
1974).
Environmental Aspects
The annual release of DCE to the environment has been
estimated in two EPA-sponsored reports. One investigation (U.S.
EPA, 1976a) estimates that 560 million Ib of DCE was released
domestically in 1973. The second report (U.S. EPA, 1975a) claims
that the actual release rate of DCE is somewhat, lower, with 163
million Ib released in 1974. This latter figure was generated in
a more careful fashion since losses from several specific cate-
gories were considered, whereas the first report used only
percentages of production and consumption. In the second EPA
report, emissions of DCE during the manufacture of end products,
principally vinyl chloride, were identified as the major source
of environmental losses. Production of DCE was cited as the next
largest emissions category. Of the two processes used to manu-
facture DCE, the: oxychlorination method was felt to emit five
102
-------
times as much DCE as the direct chlorination scheme for the same
quantity of product. The third major source of DCE emissions was
its use as a solvent (100% losses assumed). Storage and distri-
bution of DCE were identified as the last major loss category.
Refer to Table 4 for further information.
Table 4. 1,2-Dichloroethane Emissions Estimate
(based on 1974 domestic DCE production of 9,300 million Ib)
Source
End product mfg.
Source ..strength
(10b Ib)
8,500
% Loss
1.0
DCE emissions
(106 Ib)
85.0
DCE production
Oxychlorination
Direct chlorination
Solvent uses
Storage/distribution
Total
3,
5,
9,
906
394
14
300
1.
0.
100
0.
2
2
06
48.
k9.
14
6
163
3
7
Source: EPA, 1975a.
Figure 1 presents a schematic of the losses and waste
products associated with vinyl chloride production. Waste
streams 4 and 5 in the figure represent the most hazardous
process wastes associated with vinyl chloride production. These
"heavy ends" (often called DCE tars) are most commonly disposed
of via uncontrolled incineration in the United States. This is
not considered an environmentally adequate method, as controlled
incineration practices will reduce air pollution while having no
impact on water and noise pollution (U.S. EPA, 1976b).
In some European countries, DCE tars are dumped in ocean
waters (e.g., the North Sea) where the tars may have adverse
effects on the marine environment (Jensen et al., 1975). This
method of disposal is apparently not used in the United States,
although this could not be confirmed.
1,2-Dichloroethane, being a vicinal or neighboring dihalide,
is virtually unreactive in water. The half-life of DCE in water
(via chemical degradation only) is estimated to be on the order
of thousands of years (U.S. EPA, 1977b).
DCE has been found in 11 raw water locations at levels from
less than 0.2 to 3.1 yg/1 and in 26 finished water locations
(32.0 of total) at levels ranging from 0.2-6.0 yg/1 (U.S. EPA,
103
-------
in
o
z
HI
o O S~\ z
-i 9 p .-I 1—v (In) i"
|g|(^HF|
> _ JSl 1 <
TT °- » Ul
O Ul T '0:
•H
fc
XI
in
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0)
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104
-------
VENT ON REFLUX CONDENSOR (GAS)
ETHANE 0.0049
1,2-DICHLOROETHANE 0.012
METHANE 0.0049
I
HEAVY ENDS
TO AIR
1,2-DICHLOROETHANE 0.0024
1,1,2-TRICHLOROETHANE 0.004
TETRACHLOROETHANE 0.004
TARS TRACE
TO LAND
HEAVY ENDS
HEAVY ENDS 0.037
1,2-DICHLOROETHANE 0.0008
TARS 0.00005
SOLIDS ASH 0.0002
TO LAND
Figure 1. (Continued)
105
-------
1975b). A more recent EPA-sponsored study (1977c) of ambient
surface waters collected from 204 sites near heavily industrial-
ized areas across the United States identified DCE in 53 of the
samples (26% of total). The reported values ranged from 1 ppb
(detection limit) to 90 ppb (Delaware River site) (U.S. EPA,
1977c).
Data available in 1975 estimate that the atmospheric half-
life of DCE is 3-4 months (U.S. EPA, 1975c). The stability
estimate is based on the reaction of DCE with free hydroxy radi-
cals. Subsequent to the formulation of this half-life estimate,
the projected atmospheric concentration of hydroxyl radicals was
revised downward. This would imply a longer atmospheric lifetime
for DCE than formerly estimated. The expected major products of
the reaction between DCE and hydroxyl radicals are monochloro-
acetyl chloride, hydrogen chloride, and monochloroacetic acid
(U.S. EPA, 1975c).
1,2-Dichloroethane is slightly lipophilic in biological
systems and thus has a slight tendency to bioaccumulate in the
fat. However, bioaccumulation appears to be minimal (U.S. EPA,
1977b).
REFERENCES
Brem, Henry et al. The mutagenicity and DNA-modifying effect of
haloalkanes. Cancer Res. ^4:2576, 1974.
Condensed Chemical Dictionary (CCD), 9th ed. New York, Van
Nostrand Reinhold Co. 1977.
Ehrenberg, L. et al. On the reaction kinetics and mutagenic
activity of methylating and £-halogenoethylating gasoline addi-
tives. Radiat. Bot. 15_:185, 1974.
Gleason, M. N. et al. Clinical Toxicology of Commercial Pro-
ducts. Baltimore, Williams and Wilkins Co. 1969.
Gothe, R. et al. Trapping with 3,4-dichlorobenzenethiol of
reactive metabolites formed in vitro from the carcinogen vinyl
chloride. Ambio 3_:234, 1974. (As cited in McCann et al. , 1975)
Hardie, D. W. F. Chlorocarbons and chlorohydrocarbons. In Kirk-
Othmer Encyclopedia of Chemical Technology, vol. 5. New York,
Interscience Publishers. 1967. p. 149.
Heppel, L. A. et al. Toxicology of dichloroethane: I. Effect on
the cornea. AMA Arch. Ophthalmol. 3J[:391, 1944. (As cited in
Irish, 1963)
106
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Heppel, L. A., and V. T. Porterfield. Enzymic dehalogenation of
certain brominated and chlorinated compounds. J. Biol. Chem.
17_6:763, 1948. (As cited in McCann et al. , 1975)
Irish, D. D. Halogenated hydrocarbons: I. Aliphatic. In F. A.
Patty (ed.), Industrial Hygiene and Toxicology, vol. II. New
York, Interscience Publishers. 1963. p. 1280.
Jensen, S. et al. On the chemistry of EDC-tar and its biological
significance in the sea. Proc. R. Soc. London Ser. B 189; 333,
1975.
Lawrence, W. H. et al. Toxicity profile of chloroacetaldehyde.
J. Pharm. Sci. 6^:19, 1972. (As cited in McCann et al., 1975)
Lawenheim, Frederick A., and Marguerite K. Moran. Faith, Keyes,
and Clark's Industrial Chemicals, 4th ed. New York, John Wiley
and Sons. 1975. p. 392.
Malaveille, C. et al. Mutagenicity of vinyl chloride, chloro-
ethylene oxide, chloroacetaldehyde, and chloroethanol. Biochem.
Biophys. Res. Commun. 6_3_:363, 1975. (As cited in McCann et al. ,
1974)
McCann, Joyce et al. Mutagenicity of chloroacetaldehyde, a
possible metabolic product of 1,2-dichloroethane (ethylene
dichloride), chloroethanol (ethylene chlorohydrin), vinyl chlo-
ride and cyclophosphamide. Proc. Natl. Acad. Sci. U.S.A. 72(8);
3190, 1975.
NIOSH (National Institute of Occupational Safety and Health).
Criteria for a Recommended Standard. Occupational Exposure to
Ethylene Dichloride. 1976.
Olson, W. A. et al. Induction of stomach cancer in rats and mice
with halogenated aliphatic fumigants. J. Natl. Cancer Inst.
51(6):1993, 1973.
Rapoport, I. S. Reaction of gene proteins with ethylene chlo-
ride. Akad. Nauk. SSSR Dokl. Biol. Sci. 134:745, 1960. (As
cited in McCann et al., 1975)
Rosenbaum, N. D. Ethylene dichloride as an industrial poison.
Gig. Sanit. 12_(2):17, 1947. (As cited in NIOSH, 1976)
Rosenkranz, S. et al. 2-Haloethanols: Mutagenicity and reac-
tivity with DNA. Mutat. Res. 2^:367, 1974. (As cited in McCann
et al., 1975)
107
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Shakarnis, V. F. Induction of X-chromosome nondisjunction
and recessive sex-linked lethal mutations in females of
Drosophila melanogaster by 1,2-dichloroethane. Genetica
5_:89, 1969. (As cited in McCann et al. , 1975)
SRI. (Stanford Research Institute). Chemical Economics
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Urosova, T. P. About a possibility of dichloroethane absorption
into milk of nursing women when contacted under industrial
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1976)
U.S. Environmental Protection Agency (U.S. EPA). Assessment
of Ethylene Dichloride as a Potential Air Pollution Problem,
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U.S. Environmental Protection Agency. Draft Report for
Congress: Preliminary Assessment of Suspected Carcinogens
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U.S. Environmental Protection Agency. Report on the Problem
of Halogenated Air Pollutants and Stratospheric Ozone.
ESRL-ORD, EPA 600/9-75-008, 1975c.
U.S. Environmental Protection Agency. Scoring of Organic
Air Pollutants: Chemistry, Production and Toxicity of
Selected Synthetic Organic Chemicals. 1976a.*
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U.S. Environmental Protection Agency. A Study of Industrial
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U.S. Environmental Protection Agency. Review of the Environ-
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*This document was prepared for the U.S. Environmental Protection
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Manufacturing Chemicals.
108
-------
U.S. Environmental Protection Agency. Monitoring to Detect
Previously Unrecognized Pollutants in Surface Waters. EPA
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U.S. International Trade Commission. Synthetic Organic Chemi-
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Voogd, C. E. et al. On the mutagenic action of dichlorovos.
Mutat. Res. 16^413, 1972. (As cited in McCann et al. ,
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Voogd, C. E. Mutagenic action of epoxy compounds and several
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al., 1975)
14
Yllner, S. Metabolism of 1, 2-dichloroethane- C in the
mouse. Acta Pharmacol. Toxicol. ^:257, 1971. (As cited
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109
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CHEMICAL HAZARD INFORMATION PROFILE
N,N-dimethyIformamide
Date of report: April 13, 1978
This chemical was chosen for study because of the
exposure potential associated with its use as a solvent and
because of an inquiry regarding its health effects.
The following recommendations are made regarding further
OTE evaluation of the possible health or environmental
hazards of N,N-dirnethy If ormamide (DMF) :
(1) Check TSCA inventory for production volume—Good
production figures are not currently available.
(2) Consider need for testing—The use patterns of DMF
along with its potential for a greatly increased
market imply a potential for widespread exposure.
Also, the results of teratogenicity studies performed
to date are somewhat conflicting.
(3) Require Section 8(a) submission--Determine the
extent to which DMF is used in consumer products.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
N,N-dimethyIformamide is a liquid which boils at 153°C
and has a vapor pressure of 3.7 mm Hg. It is infinitely
soluble in water, alcohol, and ether (Weast, 1971; MITRE
Corp., 1976).
Production and Use
Dimethylformamide (DMF) is produced commercially by
reacting dimethylamine and methyl formate (Louderback,
1965). Production figures for DMF itself could not be found
because there are only two producers (U.S. ITC, 1975).
However, the EPA Organic Chemical Producer's Data Base does
contain data on DMF production. In 1972, SRI estimated that
about half the dimethylamine produced was used for the
manufacture of DMF and dimethylacetamide; 96 million Ib of
dimethylamine was produced in 1972.
110
-------
Dimethylformamide is a polar, relatively nonvolatile solvent
used in the manufacture of films, fibers, adhesives, and coatings.
Examples of polymer products made in this solvent are polyacrylo-
nitrile fibers, polyvinyl chloride, urethane fabric coatings, and
Orion . DMF is a component in paint strippers and is a solvent
for pigments of low solubility. These pigments include azo dyes
and nitroso compounds and are used in textiles, paper, and plas-
tics. Antifreeze gasoline additives contain small quantities of
DMF. DMF is used as a selective extractant in the purification
of oils and gases and is also used as catalyst and intermediate
in the production of acetals, aldehydes, esters, and other com-
pounds (Louderback, 1965).
Health Aspects
Single exposures to dimethylformamide are not particularly
hazardous, but irreversible systemic damage can occur when DMF
is inhaled or absorbed through the skin over a period of time
(Louderback, 1965).
DMF has low acute oral toxicity; the rat oral LDso is 4,200
mg/kg. Central nervous system toxicity was reported in humans
who inhaled concentrations of 20 ppm (NIOSH, 1975). In a case of
acute occupational exposure involving both inhalation and dermal
exposure, DMF caused severe abdominal pain and hepatic abnormali-
ties. Disturbed porphyrin metabolism was suggested as a possible
mechanism; other symptoms included anorexia, vomiting, dermal
irritation, hypertension, and weakness (Potter, 1973).
Among workers exposed to DMF, allergic gastritis and derma-
titis have been reported (DiLorenzo and Grazioli, 1972). DMF
enhances skin penetration (Wiles and Narcisse, 1971), so precau-
tions are normally taken to avoid skin contact. In a fiber plant
where DMF, methyl methacrylate, and acrylonitrile were present,
workers complained of skin and nervous system disorders (Stamova
et al., 1976). Workers have also noted headaches and a flushed
feeling after drinking alcohol; there is evidence that ethanol
alters DMF metabolism in rats (Hanasono et al., 1977).
Several Russian scientists have done experiments which
attempt to measure chronic health effects of nonoccupational
exposure to DMF. Measurable quantities of DMF were present in
underwear made from polyacrylonitrile fibers. Aqueous extracts
from the cloth produced no changes in blood or liver functions in
4 months in animals exposed dermally (Rapoport et al., 1974).
Shoes made from unstable polymers allowed both DMF and styrene to
migrate through the skin (Es'Kova Soskovets, 1973).
Ill
-------
Carnaghan (1967) reports that no tumors were observed after
32 months in 19 rats. DMF was administered once by gastric
intubation.
DMF can cross the placenta and does accumulate in the fetus
of rats (Sheveleva et al., 1977). DMF was applied to the skin of
pregnant rabbits during fetal organogenesis; no teratogenic
effects were seen, but slight embryotoxicity was noted (Stula and
Krauss, 1977). DMF was reported as not teratogenic to chick
embryos (reference unknown). Pregnant rats exposed via inhala-
tion produced normal fetuses; however, high doses led to a weight
loss in the fetus (Kimmerle and Machemer, 1975). Repeated doses
of DMF were teratogenic for mice; no other details were given
(Scheufler, 1976).
Although the mechanism of DMF metabolism is not understood,
it is known that the majority of DMF is eliminated within 24 hr
in humans (Kimmerle and Eben, 1975). To estimate total exposure
to DMF, the concentration of DMF and its metabolites, monomethyl-
formamide and formamide, in the urine may be measured (Barnes and
Henry, 1974). Dogs exposed chronically to 10 ppm did not accumu-
late DMF (Kimmerle and Eben, 1975). The TLV for DMF is 10 ppm
(ACGIH, 1971).
Environmental Aspects
Dimethylformamide has been found in Polish industrial waste-
water; it is not known to what extent industrial effluents are a
problem domestically (Dojlido, 1977). Due to its infinite
solubility in water, DMF does present a water treatment problem.
Romadina (1975) and Begert (1974) report that DMF can be biode-
graded by bacteria. At high DMF concentrations, though, the
bacteria are poisoned (Begert, 1975).
Dimethylformamide is listed in EPA's Chemical Spills File
and would be considered a hazardous material in the event of an
accidental spill.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists).
Cincinnati, Ohio. 1971.
Barnes, J. R., and N. W. Henry. The determination of N-methyl
formamide and N-methyl acetamide in urine. Am. Ind. Hyg. J.,
p. 84, February 1974.
Begert, A. Biological purification of dimethylformamide-contain-
ing industrial sewage. Von Wasser 43:403, 1974.
112
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Begert, A. Purification of chemical textile plant sewage.
Oesterr. Abwasser-Rundsch. _2_0:98, 1975. (Abstract)
Carnaghan, R. B. A. Br. J. Cancer 21:811, 1967. (Cited in PHS
149)
DiLorenzo, F., and C. Grazioli. Hematologic, hematochemical and
gastric function findings in workers exposed to inhalation of
dimethylformamide vapor. Lav. Um. 2_£(4):97, 1972. (Abstract)
Dojlido, J. Testing of biodegradability and toxicity of organic
compounds in industrial wastewaters. U.S. Environmental Protec-
tion Agency. Polish/U.S. Symp. Wastewater Treat. Sludge Dis-
posal. 1977. p. 122.
Es'Kova-Soskovets, L. B. Biological effect of chemical sub-
stances migrating from shoes during their wearing. Gig. Sanit.
3_8: 101, 1973. (Abstract)
Hanasono, G. K., R. W. Fuller, W. D. Broddle, and W. R. Gibson.
Studies on the effects of N,N'-dimethylformamide on ethanol
disposition and monoamine oxidase activity in rats. Toxicol.
Appl. Pharmacol. 3_9_:461, 1977.
Kimmerle, B., and A. Eben. Metabolism studies of N,N-dimethyl-
formamide: II. Studies in persons. Int. Arch. Arbeitsmed.
3_4(2):127, 1975. (Abstract)
Kimmerle, G. , and L. Machemer. Studies with N,N-dimethylforma-
mide for embryotoxic and teratogenic effects on rats after
dynamil inhalation. Int. Arch. Arbeitsmed. 34(3):167, 1975.
(Abstract)
Llewellyn, G. C., W. S. Hastings, and T. D. Kimbrough. The
effects of dimethylformamide on female mongolian gerbils, Reriones
ungulculatus. Bull. Environ. Contain. Toxicol. 1.1(5) :467, 1974.
Louderback, H. Kirk-Othmer Encyclopedia of Chemical Technology,
2nd ed., vol. 10. New York, John Wiley and Sons. 1965. p. 109.
MITRE Corp. Scoring of Organic Air Pollutants. Chemistry,
Production, and Toxicity of Selected Synthetic Organic Chemicals.
1976.
NIOSH. Registry of Toxic Effects of Chemicals, 1975 ed.
Potter, H. Phelps. Dimethylformamide-induced abdominal pain and
liver injury. Arch. Environ. Health 27^340, 1973.
113
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Rapoport, K. A., S. F. lonkina, and L. A. Mintseva. Hygienic
evaluation of underwear made of polyacrylonitrile fibers and
their mixtures with natural fiber. Gig. Sanit. 3.2^:85, 1974.
(Abstract)
Romadina, E. S. Direct action of microorganisms. Biol.
Samoochish-Chemie 2nd, 110, 1975. (Abstract)
Scheufler, H. Experimental testing of chemical agents for
embryotoxicity, teratogenicity, and mutagenicity. Biol. Rundsch.
14(14):227, 1976. (Abstract)
Schottek, W. Experimental animal studies on the toxicity of
dimethylformamide under repeated use. Acta Biol. Med. Ger.
25_(2):359, 1970. (Abstract)
Sheveleva, G. A., 0. V. Sivochalova, S. A. Osina, and L. S.
Sal'nikova. Permeability of placenta to dimethylformamide.
Akush. Ginekol. 5_:44, 1977. (Abstract)
Stamova, N., N. Ginceva, M. Spasovski et al. Labor hygiene
during the production of Bulana synthetic fibers. Khig. Zdrave-
opaz. 1£(2):134, 1976. (Abstract)
Stanford Research Institute (SRI). Chemical Economics Handbook.
Menlo Park, Calif. 1975.
Stula, E. F., and W. C. Krauss. Embryotoxicity in rats and
rabbits from cutaneous application of amide-type solvents and
substituted ureasP. Toxicol. Appl. Pharmacol. 4^(1): 35, 1977.
(Abstract)
Tanka, K. I. Toxicity of dimethylformamide to the young female
rat. Int. Arch. Arbeitsmed. 78^(2) :96, 1971. (Abstract)
Ungar, H., S. F. Sullraan, and A. J. Zuckerman. Acute and pro-
tracted changes in the liver of Syrian hamsters induced by a
single dose of aflatoxic Fl'. Br. J. Exp. Pathol. 57(2);157,
1976. (Abstract)
U.S. International Trade Commission. Synthetic Organic Chemi-
cals, United States Production and Sales. 1975.
Weast, Robert C. (ed.). CRC Handbook of Chemistry and Physics,
52nd ed. Cleveland, The Chemical Rubber Co. 1971.
Wiles, J. S., and J. K. Narcisse. The acute toxicity of dimethyl-
amides in several animal species. Am. Ind. Hyg. Assoc. J.
32^(8) :539, 1971. (Abstract)
114
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CHEMICAL HAZARD INFORMATION PROFILE
Dinitrosopentamethylenetetramine
Date of report: June 1, 1978
This chemical was chosen for study because of worker
complaints received by OSHA. Workers at a dinitrosopentamethylene-
tetramine (DNPT) plant complained of fainting, dizziness,
cyanosis, and convulsions.
It is recommended that judgment on DNPT be deferred
until OSHA completes its report on occupational health
problems associated with the chemical. The OSHA study
should provide a much better characterization of the problem
than is currently available. This CHIP should be updated
based on the additional information obtained.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Synonyms: DNPT; 3,7-dinitroso-l,3,5,7-tetraazabicy-
clononane
CAS No.: 101-25-7
A structural diagram of DNPT is shown below:
r
CH2 N-N.O
CH2 N CH2
DNPT is a light-yellow solid which decomposes at 207°C.
When used with rubber or plastics, its decomposition temperature
is lowered to 130-190°.C. It is slightly soluble in water,
alcohol, and benzene, and dissolves readily in dimethylformamide
(IARC; 1976; McCaleb, 1978).
115
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Production and Use
IARC reports U.S. consumption of DNPT at 3 million Ib in
1970. SRI estimates annual production at 2-3 million Ib. The
U.S. ITC (1975) reports one producer, Stepan Chemical Co.
DNPT is used as a blowing agent in rubbers and plastics.
Natural and synthetic unicellular rubber, which is made using
DNPT, is used as carpet underlay, weatherstripping, insulation,
shoe lining, and cushioning. DNPT is also an effective blowing
agent for polyvinyl chloride plastisols and epoxy, polyester, and
silicone resins.
DNPT is produced from hexamine (hexamethylenetetramine),
HCl, and sodium nitrite. During its use as a blowing agent,
acidic substances such as phthalic anhydride and ethylene glycol
are often added to accelerate the reaction and to lower the
temperature of the decomposition process. Decomposition products
are not fully elucidated; possible ones are amines, water,
nitrous oxide, nitrogen gas, formaldehyde, and ammonia. A fishy
odor, due to the amines, and the high decomposition temperature
make DNPT an unsuitable blowing agent for many plastics, though
it is the most widely used blowing agent for rubber sponges
(McCaleb, 1978).
Health Aspects
The chemical was referred to us by OSHA (Stewart, 1978),
which is investigating complaints of fainting, dizziness, cya-
nosis, and convulsions at a DNPT production plant. All ten
workers reported one or more symptoms. An OSHA medical team
plans to carefully inspect the plant during the week of May 30,
1978.
No health effects information was found aside from the IARC
report, which is summarized below.
The rat oral LD5Q was 940 mg/kg. A dose of 80 mg/kg injected
intraperitoneally for 30 days was tolerated. Higher doses pro-
duced toxic effects within the central nervous system, including
depression of conditioned reflexes and tonic and clonic spasms
(Desi et al., 1967).
No tumors were induced in female rats given a single oral
dose of 90 mg DNPT within 6 months (Griswold et al., 1966), nor
were tumors induced after 18 months in 15 male and 15 female rats
given 9 mg DNPT by oral gavage daily for 1 year (Weisburger et
al., 1966). Rats fed 0.03, 1, 3, or 9 mg DNPT 4 days/week for a
year did not have an increased tumor incidence after 18 months
(Hadidian et al., 1968).
116
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Boyland et al. (1968) reported that of 24 male rats given
weekly IP injections of 25 mg DNPT for 26 weeks, 13 survived over
16 months. One developed a hepatoma and another developed a
pituitary tumor. However, one of the controls developed a
hepatoma, and IARC concluded that DNPT is not a rat carcinogen by
oral administration or by intraperitoneal injection.
Environmental Aspects
No information was found in the sources consulted on
environmental fate or effects of DNPT.
REFERENCES
Boyland, E. et al. Carcinogenic properties of certain rubber
additives. Eur. J. Cancer £:233, 1968.
Desi, F. et al. Investigations on the nervous effects of N,N-
dinitrosopentamethylenetetramine (Mikrofor) in rats. Med. Lav.
5_8:22, 1967.
Griswold, P. P. et al. On the carcinogenicity of a single intra-
gastric dose of hydrocarbons, nitrosamines, aromatic amines,
dyes, coumarins, and miscellaneous chemicals in female Sprague-
Dawley rats. Cancer Res. 2£:619, 1966.
Hadidian, Z. et al. Tests for chemical carcinogens. J. Natl.
Cancer Inst. 4_1:985, 1968.
International Agency for Research on Cancer (IARC). Evaluation
of Carcinogenic Risk of Chemicals to Man, vol. 11. 1976. p.
241.
McCaleb, Kirt, at SRI International, Menlo Park, Calif., personal
communication, May 18, 1978.
Stewart, Trish, OSHA, personal communication, May 18, 1978.
U.S. International Trade Commission (U.S. ITC). 1975.
Weisburger, J. H. et al. New carcinogenic nitrosamines. Natur-
wissenschaften 53:508, 1966.
Bibliography
Encyclopedia of Polymer Science and Technology, vol. 2, Blowing
Agents (Chapter) has a few pages on DNPT.
Reed, R. A. Plastic progress. London, Iliffe and Sons Ltd.
1955. p. 51-80.
R. A. Br. Plast. J33_(10) :469, 1969.
Rubber Age, February 1976, p. 22.
Rubber World Blue Book 1975. Useful for trade names.
117
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CHEMICAL HAZARD INFORMATION PROFILE
2,4-Dinitrotoluene
Date of report: March 9, 1978
This chemical was chosen for study because of a determina-
tion of its carcinogenicity in an NCI bioassay.
If the contractor report on nitroaromatics does not provide
adequate use information on 2,4-dinitrotoluene, TSCA Section 8(a)
submissions should be required. Use information will be neces-
sary for exposure estimates. A revised Chemical Hazard Informa-
tion Profile should be prepared when satisfactory use information
is obtained.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily
follows that this repott may not reflect all available informa-
tion on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Chemical Identity
2,4-Dinitrotoluene ^Hg^O^ exists as yellow crystalline
needles at room temperature. Its melting range is from 69.5 to
70.5°C. 2,4-Dinitrotoluene (2,4-DNT) decomposes at 300°C. Its
molecular weight is 182.1, and its density is 1.521 (at 15°C).
2,4-DNT is sparingly soluble in water (0.027 g/100 ml at 22°C)
and is soluble in ether and in alcohol. Synonyms for 2,4-DNT
(CAS No. 121-14-2) include 2,4-dinitrotoluol and l-methyl-2,4-
dinitrobenzene. 2,4-DNT is considered a moderate fire and
explosion risk. It can be detonated only by a strong initiator
but may become an explosion hazard when involved in fire (Sax,
1968) .
Production and Use
Dinitrotoluene can be produced by batch or continuous pro-
cess. The starting material is usually 2- or 4-nitrotoluene,
although toluene itself is sometimes used. The dinitrotoluene
resulting from use of 2-nitrotoluene will contain both the 2,4-
and 2,6-isomers. The continuous process may consist of several
reactors joined in series. The raw materials (toluene/nitro-
toluene and an acid mixture of H2S04 and HN03) are added only to
118
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the first reactor. Successive chambers provided additional
reaction time. This exothermic reaction has an overall yield of
roughly 96%. The acid is then removed. The crude dinitrotoluene
is washed and neutralized. Most of the product that is formed
goes directly to a reduction step, forming diaminotoluene; how-
ever, some material may be distilled if high-purity 2,4-dinitro-
toluene is needed (EPA, 1976).
Shipping solids, such as 2,4-DNT, in a molten state in tank
cars is a common practice. The price of 2,4-DNT was 22.5C/lb (in
tanks) in 1975 (EPA, 1976).
Manufacture of toluene diisocyanate consumes much of the
2,4-DNT produced. In 1976, 560 million Ib of toluene diiso-
cyanate was produced. This production consumed roughly 389
million Ib of toluene (SRI, 1976). A total of 389 million Ib of
toluene would produce approximately 740 million Ib of 2,4-DNT,
assuming 96% yield (U.S. EPA, 1976). 2,4-DNT is also used as a
gelatinizing and waterproofing agent in explosives and as a dye
intermediate (SRI, 1976).
Year
U.S. DNT production
Substance
Pounds produced
1971
1972
1973
1974
1975
2,
2,
2,
2,
2,
2,
4-
4-
4-
4-
(and
(and
(and
(and
2
2
2
2
,
r
/
i
6-)
6-)
6-)
6-)
DNT
DNT
DNT
DNT
4-DNT
4-
(and
2
i
6-)
DNT
352,
433,
471,
522,
308,
272,
746
885
237
842
257
610
,000
,000
,000
,000
,000
,000
Source: U.S. ITC, 1973-77.
Based upon the growth projections for the major uses of DNT,
demand should increase by 6.5 to 7.5% per year (EPA, October
1977).
2,4-DNT is produced by Air Products & Chemicals, Inc.,
Pensacola, Fla., and by Rubicon Chemicals, Inc., Geismar, La.
2,4- (and 2,6-) DNT is produced by E. I. du Pont, Deepwater,
N.J., and by Mobay Chemicals Corp., Cedar Bayou, Tex., and New
Martinsville, W. Va. (SRI, 1975). Other companies may manu-
facture 2,4-DNT as a chemical intermediate for captive use.
Health Aspects
The TLV.(and TWA) of 2,4-DNT is 1.5 mg/m3 (air). It may be
absorbed through intact skin. Symptoms of DNT exposure include
119
-------
headache, vertigo, fatigue, shortness of breath, anorexia,
palpitation, arthralgia, insomnia, tremor, and paralysis (ITII,
1976). Advanced cases show symptoms such as jaundice and second-
ary anemia (ACGIH, 1971).
Exposure of rats to 50 mg/kg 2,4-DNT (orally) or to 200 ppm
2,4-DNT (1-hr inhalation) produced no mortality. The oral LD50
is 268 mg/kg for rats and 1,625 mg/kg for mice. There is evi-
dence that a high-fat, low-protein diet renders rats more suscep-
tible to TNT and DNT poisoning. Application of 200 mg/kg to the
skin of rabbits did not cause mortality, nor was it corrosive to
the skin. The LD5Q for oral administration of 2,4-DNT to cats is
27 mg/kg (EPA, 1976). NCI has conducted a bioassay of 2,4-DNT.
It was fed to rats at 0.02% or 0.008% of their diet. Both
levels increased the incidence of fibroma of the skin and subcu-
taneous tissue in male rats. The high dose caused a statistically
significant incidence of fibroadenoma of the mammary gland in
female rats. Mice fed 0.04% or 0.008% 2,4-DNT did not show
tumors which could be attributed to the compound. NCI considers
the results of this bioassay to be positive.
Environmental Aspects
The aquatic toxicity rating of 2,4-DNT is 100 to 10 ppm for
96 hr of exposure (NIOSH, 1976). 2,4-DNT depressed or killed
colonies of Lemna perpusilla (an aquatic flowering plant) at
concentrations of 1 ppm and above.
Nitroaromatics are, generally, very stable in water under
neutral conditions. 2,4-DNT is an o-alkyl nitroaromatic com-
pound, and therefore is probably susceptible to photochemical
alteration since such compounds isomerize to highly colored
compounds which may react further (EPA, 1976).
EPA has identified 2,6-DNT in drinking water. Kite (1961)
detected 2,4-DNT in the red water wastes from a TNT plant (Pica-
tinny Arsenal, Dover, N.J.) by using solvent extraction, column
chromatography, and infrared spectrometry. Investigators have
found DNT in the wastewater effluents of other TNT plants and in
the plant, the raw wastes, and the pond effluent of an explosives
plant (EPA, 1976) .
Biodegradation experiments conducted using microorganisms in
soil, compost, or moved from a catalytic cracking plant waste
lagoon, adapted to phenol, showed that the ratio of the test
oxygen uptake rate to the endogenous rate was nearly 2.5 for 2,4-
DNT. This implies that it is biodegradable to some degree. In
another study, Soviet scientists estimated that 95 to 97% of 2,4-
DNT was removed after the second stage of activated sludge
digestion (EPA, 1976). Enriched pure soil culture will slowly/
partially degrade 2,4-DNT in soil.
120
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Most of the DNT produced is used captively. However, based
on the presence of DNT in sewage wastes from TNT and explosives
manufacturing plants, environmental and water supply contamina-
tion seems to be a distinct possibility.
REFERENCES
American Conference of Governmental Industrial Hygienists (ACGIH).
Documentation of the Threshold Limit Values, 3rd ed. 1971.
International Technical Information Institute (ITII). Toxic and
Hazardous Industrial Chemicals Safety Manual. Tokyo. 1976.
Kite, D., Jr. Air and stream pollution control: Preliminary
survey of thermal methods for trinitrotoluene red water disposal.
1961. (As cited in U.S. EPA, 1976)
NIOSH. Registry of Toxic Effects of Chemical Substances, 1976
ed.
Sax, N. Irving. Dangerous Properties of Industrial Materials.
New York, Van Nostrand Reinhold Co. 1968.
Stanford Research Institute (SRI). Directory of Chemical Pro-
ducers. Menlo Park, Calif. 1975.
SRI. Chemical Economics Handbook. Menlo Park, Calif. 1976.
U.S. Environmental Protection Agency (U.S. EPA). Investigation
of Selected Potential Environmental Contaminants: Nitroaromatics.
June 1976.
U.S. Environmental Protection Agency. Information Profiles on
Potential Occupational Hazards. October 1977.
U.S. International Trade Commission (U.S. ITC). Synthetic
Organic Chemicals, U.S. Production and Sales, 1973-1977.
121
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CHEMICAL HAZARD INFORMATION PROFILE
Ethanolamines
Date of report: April 14, 1978
This group of chemicals was chosen for study because of
the potential for nitrosamine contamination.
The following recommendations are made regarding further
OTE evaluation of the possible health or environmental
hazards of ethanolamines:
(1) Proceed to Phase I report—Potential problems with
substances containing ethanolamines are sufficiently
serious and sufficiently characterized to warrant
further assessment.
(2) Require Section 8 (a) submissions—Quantitative
information on use patterns will better define the
exposure profile.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Ethanolamines have a low vapor pressure; triethanolamine
and diethanolamine are white solids, while monoethanolamine
is a clear liquid. These compounds are miscible in water
and alcohol and insoluble in ether (Hart, 1967).
Production and Use
Ethanolamines are produced commercially by reacting
aqueous ammonia with ethylene oxide. Annual production is
as follows: monoethanolamine, 83 x 10 lb; diethanolamine,
86 x 10 lb; and triethanolamine, 89 x 10 .
The consumption pattern for these three compounds is
similar. In the petroleum and natural gas industry, monoethanolamine
and diethanolamine are used to remove acidic gases. Ethanolamines
are used as emulsifiers and dispensing agents in a variety of
cosmetics including cold cream and shaving cream. Ethanolamines
122
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are used in the manufacture of detergents for wool manufacture,
drycleaning, cosmetics/ and household use. As surface-active
ingredients, ethanolamines are used in the manufacture of waxes,
polishes, and cutting fluids. Some fruit-ripening agents contain
a mixture of ethanolamines, and they are also used to solubilize
herbicides. Finally, ethanolamines are used as intermediates in
the production of morpholine, resins, and plasticizers (Hartung
and Cornish, 1968; SRI, 1975).
Health Aspects
Ethanolamines are generally considered to have low acute
toxicity. The oral LD5Q values for rats are (NIOSH, 1976):
monoethanolamine, 2,100 mg/kg; diethanolamine, 710 mg/kg; and
triethanolamine, 8,680 mg/kg.
However, ethanolamines are irritating, and triethanolamine
may be sensitizing to the skin and mucous membranes (Lopukhova,
1964).
An occupational standard has been set only for monoethanol-
amine. The TLV is 3 ppm (ACGIH, 1971).
Ethanolamines are a normal constituent of human urine; they
are metabolized rapidly and are ultimately incorporated into the
phospholipids of the liver and kidney (Taylor and Richardson,
1967). There is one known occupational case of acute poisoning
by monoethanolamine in which toxic liver damage and chronic hepa-
titis occurred (Jindrichova and Urban, 1971). In subacute rodent
feeding studies, all three compounds induced liver and kidney
weight changes, and diethanolamine caused fatty degeneration of
the liver (Sutton, 1963; Hartung and Cornish, 1968). Other
pathological changes included inhibition of cholinesterase by all
ethanolamines (Hartung and Cornish, 1968).
Bose (1972) showed that triethanolamine induced meiotic
irregularities in onion cells. However, in another study (SRI,
1977) monoethanolamine did not affect meiosis in onions and did
not induce point mutations in a bacterial species. SRI experts
do not believe that either of these systems has been adequately
characterized as a screen for mammalian gene damage.
An industry study showed that hair dye with a base contain-
ing 22% monoethanolamine did not increase the incidence of birth
defects in dogs, rabbits, or rats. The rats and dogs were
exposed orally, and the rabbits by gavage (Wernick et al.,
1975).
Kostrodymova et al. (1976) reported that a triethanolamine
solution was not carcinogenic to rats exposed via the skin; no
other details were given. Grinding fluid containing triethanol-
123
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amine and sodium nitrite at gastric pH formed N-nitrosodiethanol-
amine (Zingmark and Rappe, 1976). Druckery et al. (1963) fed
nitrosodiethanolamine intermittently to rats for 41 weeks, and
all developed liver cancer. N-nitrosodiethanolamine has been
found at levels as high as 48 ppm in cosmetics and toiletry
products (C&E News, 1977). Enviro Control Inc. has a contract
with NIOSH to study the carcinogenic effects of hydraulic and
cutting fluids which contain diethanolamine and nitrite (Tox-
tips, November 1977).
Environmental Aspects
The MITRE Corp. (1976) reports an annual environmental
release rate for diethanolamine and triethanolamine as 36 million
Ib for each compound.
The aquatic toxicity ratings indicate that diethanolamine is
an "insignificant hazard" and that monoethanolamine and tri-
ethanolamine are "practically nontoxic" (NIOSH, 1976).
Apostol (1975) reports that he first noted acute effects in
aquatic organisms at 100 mg/1 and chronic effects at 1 mg/1. The
most sensitive organisms were daphnia, ciliated protozoa, and
amoeba.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists) .
Documentation of Threshold Limit Values. Cincinnati, Ohio.
1971.
Apostol, S. Ethanolamine toxicity to aquatic invertebrates.
Stud. Cercet. Biol. !27(4):345, 1975. (Cited in Chem. Abstr.
£5:73051G)
Bose, S. Preliminary studies on triethanolamine induced meiotic
irregularities in onion (Allium cepa L.) Sci. Cult. 3_8_(3) : 146,
1972.
C&E News. N-nitrosoamines found in toiletry products. March
28, 1977.
Druckrey, H., R. Preussmann, and D. Schmahl. Carcinogenicity and
chemical structure of nitrosamines. Acta. Un. Int. Cancer 19(3-
4):510, 1963.
Hart, A. W. Alkanolamines. In Kirk-Othmer Encyclopedia of
Chemical Technology, vol. 1. 1967. p. 810-824.
124
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Hartung, R., and H. H, Cornish. Cholinesterase inhibition in the
acute toxicity of alkyl-substituted 2-aminoethanols. Toxicol.
Appl. Pharmacol. 128:486, 1968.
Jindrichova, J., and R. Urban. Acute monoethanolamine poisoning.
Prac. Lek. 2_3(9) :314, 1971. (Cited in KEEP 72;09648)
Kostrodymova, G. M., V. M. Voronin, and N. N. Kostrodymov.
Toxicity from the complex action and the possibility of carcino-
genic and cocarcinogenic properties of triethanolamine. Gig.
Sanit. 3^20, 1976. (Cited in Chem. Abstr. 84;174886t)
Lopukhova, K. A. Current problems on the effect of synthetic
detergents on the skin. Gig. Tr. Prof. Zabol. 8^(12) : 38-42,
1964.
MITRE Corp. Scoring of Organic Air Pollutants. Chemistry,
Production, and Toxicity of Selected Synthetic Organic Chemicals.*
1976.
NIOSH. Registry of Toxic Effects of Chemical Substances. 1976.
SRI (Stanford Research Institute). A Study of Industrial Data on
Candidate Chemicals for Testing. EPA-560/5-77-006, August 1977.
p. 3-179.
Button, W. L. Aliphatic and alicyclic amines. In F. A. Patty
(ed.), Industrial Hygiene and Toxicology, 2nd ed. New York,
Interscience Publishers. 1963.
Taylor, R. J., Jr., and K. E. Richardson. Ethanolamine metabolism
in the rat. Proc. Soc. Exp. Biol. Med. 124 (1);247, 1967.
Tox-tips. Notice of Research Project. November 1977.
U.S. ITC (U.S. International Trade Commission). Synthetic Organic
Chemicals, United States Production and Sales, 1975.
Wernick, T., B. M. Lanman, and J. L. Fraux. Chronic toxicity,
teratologic, and reproduction studies with hair dyes. Toxicol.
Appl. Pharmacol. 32^(3): 450, 1975.
Zingmark, P. A., and C. Rappe. On the formation of N-nitrosodi-
ethanolamine from a grinding fluid under simulated gastric
conditions. Ambio 5(2): 80, 1976.
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some informa-
tion is not possible. The environmental release data were taken
from NSF/Rann Research Program on Hazard Priority Ranking of
Manufacturing Chemicals.
125
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CHEMICAL HAZARD INFORMATION PROFILE
Ethylamines
Date of report: April 1, 1978
These chemicals were chosen for study because of their
potential for being nitrosated and thereby forming nitrosamines.
Certain nitrosamines are known carcinogens.
The following recommendations are made regarding further
OTE evaluation of the possible health or environmental
hazards of ethylamines:
(1) Refer to OSHA—Toxic effects have been seen in
both humans and test animals at ethylamine concentrations
below the current OSHA standard.
(2) Refer to OPP--Diethylamine was found as a degradation
product of a commercial pesticide. This diethylamine
was subsequently nitrosated to form diethylnitrosamine.
(3) Refer to the Office of Air Quality Planning and
Standards-—Significant amounts of amines may be
released into the ambient air from manufacturing
sites.
(4) Require Section 8(a) submission—Determine the
presence ox" ethylamines in consumer products and
revise this Chemical Hazard Information Profile
accordingly.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents., Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Monoethylamine is a gas which condenses at 16.6°C.
Diethylamine is a volatile liquid which boils at 55.5°C;
triethylamine is also a liquid and boils at 89.3°C. All
three compounds are soluble in water, have an ammoniacal
odor, and are quite basic (MITRE Corp., 1976). The respective
PKb and vapor pressure values (mmHg at 20°C) for these
compounds are as follows: monoethylamine 3.36; diethylamine
3.39, 195; and triethylamine 3.29 and 53.5 (Button, 1963).
126
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Production and ^
In 1975, 12.4 million Ib of diethylamine was produced. In
the preceding year over 46 million Ib of all ethylamines, exclud-
ing diethylamines, was manufactured. This figure may include
some salts but should reflect the combined amount of monoethyl-
amine and triethylamine manufactured in 1974 (U.S. ITC, 1974,
1975).
The ethylamines are used mostly as chemical intermediates
for the production of pesticides, textile chemicals, medicinals,
and corrosion inhibitors. Detailed breakdowns of use categories
are not available, but some specific uses are listed below.
Monoethylamine (MEA) is used as an intermediate in the
manufacture of the following chemicals: triazine herbicides,
1,3-diethylthiourea (a corrosion inhibitor), ethylaminoethanol,
4-ethylmorpholine (urethane foam catalyst), ethyl isocyanate, and
dimethylolethyltriazone (agent used in wash-and-wear fabrics).
The cuprous chloride salts of MEA are used in the refining of
petroleum and vegetable oil.
Diethylamine (DBA) is used in the manufacture of the follow-
ing chemicals: diethyldithiocarbamate and thiourams (rubber
processing accelerators), diethylaminoethanol (medicinal inter-
mediate) diethylaminopropylamine (epoxy curing agent), N,N-
diethyl-m-toluamide (insecticide), and 2-diethylaminoethylmeth-
acrylate.
Triethylamine (TEA) is used as a corrosion inhibitor in
paint removers based on methylene chloride or other chlorinated
solvents. TEA is used to solubilize 2,4,5-T in water and serves
as a selective extractant in the purification of antibiotics.
Octadecyloxymethyltriethylammonium chloride, an agent used in
textile treatment, is manufactured from TEA (SRI, 1975).
Health Aspects
Ethylamines produce strong local irritation when inhaled or
on contact with the skin. Inhalation of small quantities of
monoethylamine or triethylamine may cause death or permanent
injury. Human effects are usually local; inhalation may cause
eye irritation, lacrimation, conjunctivitis, nose and throat
irritation, or coughing. Systemic symptoms such as headache,
nausea, faintness, and anxiety may result from inhalation of
ethylamines (Sax, 1975).
Rat oral LDso values are as follows; monoethylamine, 400
mg/kg; diethylamine, 540 mg/kg; and triethylamine, 460 mg/kg
(NIOSH, 1975)1
127
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Brieger and Hodes (1951) exposed rabbits to 50 or 100 ppm
ethylamines for 6 weeks. At the higher dose all three compounds
produced degenerative changes in the liver, lungs, and kidneys.
Only triethylamine weakened the heart. Eye irritation and slight
liver damage were reported at the lower dose for each compound.
In a 5-year Russian study of children who lived near a
factory which released monoethylamine, increases in acute respi-
ratory, ear, and mastoid infections were noted. Additional
changes reported were enhanced blood cholinesterase activity,
disturbed porphyrin metabolism, and an elevated number of eye
infections. The mean diurnal atmospheric concentration of MEA
was 0.037 mg/m3 (0.02 ppm), with a maximum of 0.293 mg/m3 (0.16
ppm). In a 3-month study, rats were exposed to 3.69 mg/m3 (2.0
ppm). A decrease in blood cholinesterase activity and changes in
porphyrin metabolism were seen. A no-effect level was seen at
0.01 mg/m3 (0.005 ppm) (Tkachev, 1969).
Hussain and Ehrenberg (1974) showed that a combination of
monoethylamine and sodium nitrite is significantly more mutagenic
than either compound alone. In this assay, E. coli mutated to
streptomycin independence. Isakova et al. (1971) exposed rats to
an ambient concentration of 1 mg/m3 (0.25 ppm) triethylamine for
3 months. The number of rats having cells with an abnormal
number of chromosomes in the bone marrow increased.
The major reason for our concern with ethylamine is that
under conditions found in the digestive tract, diethylnitrosa-
mine, an animal carcinogen, may be formed. Sodium nitrite and
the HCl salt of diethylamine were incubated in human gastric
juice (pH 1.2-1.9), and measurable amounts of diethylnitrosamine
(DEN) were found. DEN was found in the stomachs of rabbits and
cats who had been fed diethylamine and nitrite (Sen et al.,
1969). Schweinsberg and Sander (1972) showed that nitrous acid
and tertiary amines react to form nitrosamines, but much less is
formed when compared to the corresponding secondary amine. In a
1-year feeding study, rats developed no tumors after exposure to
both triethylamine and nitrite. Sander et al. (1968) showed that
the amount of nitrosamine formed from a secondary amine depends
on the basicity of that amine. Since the ethylamines are quite
basic, one would expect a small amount of diethylnitrosamine to
be formed. In a long-term feeding study, DEN produced liver
tumors in 18 of 20 guinea pigs after 30 months. However, two
groups fed combinations of diethylamine and nitrite suffered no
ill effects other than weight loss (Sen et al. , 1975).
The TLV values for occupational exposure in the U.S. are
monoethylamine, 10 ppm; diethylamine, 25 ppm; and triethylamine,
25 ppm (ACGIH, 1971).
128
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Environmental Aspects
Monoethylamine is a normal constituent of human urine
(Asatoor, 1969), and both monoethylamine and diethylamina
are present in edible fish (Gruger, 1972). Little additional
work has been done on the metabolism of ethylamines.
Normal commercial amounts of the pesticide diethyldithio-
carbamate were converted to diethylamine in soil; measurable
amounts of diethyInitrosamine were found (Tate and Alexander,
1974). Hosier (1974) showed that in a laboratory setting
with pure water and no other organism, both MEA and DEA
inhibit the growth of fresh-water algae. NIOSH's Aquatic
Toxicity Rating ranks all three compounds as "slightly
toxic."
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists)
Documentation of Threshold Limit Values. 1971.
Asatoor, A. M. Tea as a source of urinary ethylamine.
Nature 2]JD(5043) : 1358, 1969.
Brieger, H., and W. A. Hodes. Toxic effects of exposure to
vapors of aliphatic amines. Arch. Ind. Hyg. Occup. Med.
3_:287, 1951. (Cited in Button and PHS 149)
Gruger, E. H. Chromatographic analyses of volatile amines
in marine fish. J. Agr. Food Chem. ^£(4):781, 1972.
Hussain, S., and L. Ehrenberg. Mutagenicity of primary
amines combined with nitrite. Mutat. Res. 2^6:419, 1974.
Isakova,.G. K., B. Y. Ekshtat, and Y. Y. Kerkis. Mutagenic
action of chemical substances in substantiation of hygienic
standards. Gig. Sanit. 3J5(11):9, 1971.
MITRE Corp. Scoring of Organic Air Pollutants. Chemistry,
Production, and Toxicity of Selected Organic Chemicals.
1976.*
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some informa-
tion is not possible. The environmental release data were taken
from NSF/Rann Research Program on Hazard Priority Ranking of
Manufacturing Chemicals.
129
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Mosier, A. R. Effect of cattle feedlot volatiles, aliphatic
amines, on Chlorella ellipoidea growth. J. Environ. Qual.
3_(1):26, 1974.
NIOSH. Registry of Toxic Effects of Chemical Substances.
1975.
Sander, J., F. Schweinsberg, and H. Menz. Formation of
carcinogenic nitrosamines in the stomach. Hoppe-Seyler's Z.
Physiol. Chem. 3^9 (12):1691, 1968.
Sax, N. I. Dangerous Properties of Industrial Materials,
4th ed. New York, Van Nostrand Reinhold. 1975.
Schweinsberg, F. , and J. Sander. Carcinogenic nitrosamines
from simple aliphatic tertiary amines and nitrite. Hoppe-
Seyler's Z. Physiol. Chem. 353(11);1671, 1972.
Sen, N. P., D. C. Smith, and L. Schivenghamer. Formation of
N-nitrosamines from secondary amines and nitrite in human
and animal gastric juice. Food Cosmet. Toxicol. 7_(4):301,
1969.
Sen, N. P. et al. Failure to induce tumors in guinea pigs
after concurrent administration of nitrite and diethylamine.
Food Cosmet. Toxicol. 13_(4):423, 1975.
SRI (Stanford Research Institute). Chemical Economics
Handbook. Menlo Park, Calif. 1975.
Sutton, W. L. Aliphatic and alicyclic amines. Iri F. A.
Patty (ed.), Industrial Hygiene and Toxicology, 2nd ed. New
York, Interscience Publishers. 1963.
Tate, R. L., and M. Alexander. Formation of dimethylamine
and diethylamine in soil treated with pesticides. Soil Sci.
•118_(5): 317, 1974.
Tkachev, P. G. Monoethylamine in the atmosphere: Hygienic
significance and standards. Gig. Sanit. ^4(8) :7, 1969.
U.S. ITC (U.S. International Trade Commission). Synthetic
Organic Chemicals, U.S. Production and Sales, 1974 and 1975.
130
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CHEMICAL HAZARD INFORMATION PROFILE
Ethylenediamine
Date of report: May 9, 1978
This chemical was chosen for study because of its
presence in consumer products (pharmaceuticals) and its
potential for nitrosamine formation.
The following recommendations are made regarding further
OTE evaluation of the possible health or environmental
hazards of ethylamines:
(1) Consider need for testing—Ethylenediamine is a
relatively high-volume, high-exposure chemical
with very limited information on toxicity.
(2) Require Section 8(a) submission—More specific
information on uses is needed for exposure estimates.
(3) Refer to CPSC—Possibly present in products under
CPSC's authority.
(4) Transmit to NIOSH on an FYI basis—NIOSH has
scheduled a criteria document for aliphatic di-
and polyamines.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendation based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Ethylenediamine (1,2-diaminoethane), C2HsN2, is a
colorless liquid (boiling point, 116-117°C) with an ammonia-
like odor. It is soluble in water and alcohol, slightly
soluble in ether, and insoluble in benzene (Hawley, 1971).
Production and Use
Ethylenediamine is produced by heating ethylene dichloride
and ammonia (Hawley, 1971). The 1978 Directory of Chemical
Producers (SRI, 1978) lists the following manufacturers and
plant capacities for ethylenediamine production:
131
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Annual capacity
(millions of Ib)
Dow Chem. U.S.A., Freeport, Tex. 30
Union Carbide Corp., Taft, La. 39
Chems. and Plastics Div., Texas City, Tex. 24
Total 93
Ethylenediamine is used by the synthetic fiber manufacturing
industry as a stabilizer in the production of caprolactam poly-
mers (Wiithrich, 1972). It is used by the pharmaceutical indus-
try as a stabilizer in aminophylline, which is used in antiasth-
matic drugs, and in Mycolog , an antibiotic cream (Provost and
Jillson, 1967).
Ethylenediamine is also used as a solvent stabilizer, as a
neutralizer in rubber products, in dyes, waxes, dimethylolethyl-
ene-urea resins, fungicides, insecticides, and asphalt wetting
agents, and in the manufacture of the chelating agent EDTA (Baer
and Ramsey, 1973; Hawley, 1971).
Health Aspects
Ethylenediamine1s action as a contact allergen is well
established. The North American Contact Dermatitis Group (1975)
compiled results of skin patch tests conducted from July 1, 1972,
to June 30, 1974. Six percent of the 3,216 patients tested
exhibited sensitivity to 1% ethylenediamine-HCl solution. Baer
and Ramsey (1973) reported patch tests performed on patients at
the New York University Skin and Cancer Unit. A 1% solution of
ethylenediamine elicited a positive response in 13.2% of the 158
patients tested.
Significant case studies involving ethylenediamine exposure
include:
(1) A patient with a history of allergic reaction to Mycolog
cream was treated with aminophylline suppositories
following hospitalization for acute dyspnea. He developed
a generalized exfoliative dermatitis. Both drugs con-
tain ethylenediamine-HCl (Petrozzi and Shore, 1976).
(2) A patient who Lad handled epoxy resins and hardeners in
an electrical appliance factory developed dermatitis
following the use of Mycolog cream. Exposure to the
Mycolog cream occurred 3 years after a 6-month exposure
to the epoxy resins and hardeners. Two other patients
developed dermatitis following repeated use of Mycolog
cream. All three patients showed sensitivity to ethy-
lenediamine in skin patch tests (Van Hecke, 1975).
132
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The OSHA standard for workplace exposure to ethylenediamine
is 10 ppm. This value is also the American Conference of Govern-
mental Industrial Hygienists' threshold limit value.
Environmental Aspects
The estimated release rate of ethylenediamine is 22.5 mil-
lion Ib per year. It is reactive toward atmospheric oxidants.
The 20-day BOD is 70% of the theoretical value (Dorigan et al.,
1976).
The 96-hr LC5Q for aquatic life (test species unknown) is
10-100 ppm (NIOSH, 1977).
Ethylenediamine is a degradation product of the agricultural
fungicide maneb. A field study was conducted to determine levels
of degradation products found on beans and tomatoes sprayed with
maneb. Fourteen days after the final application of maneb, 0.09
ppm of ethylenediamine was found on beans and 0.05 ppm was found
on tomatoes (Newsome et al., 1975).
REFERENCES
Baer, R. L. , and D. L. Ramsey. The most common contact allergens.
Arch. Dermatol. 108:74-78, 1973.
Dorigan, J., B. Fuller, and R. Duffy. Scoring of Organic Air
Pollutants. Chemistry, Production, and Toxicity of Selected
Synthetic Organic Chemicals. MITRE Corp. 1976.*
Hawley, G. G. (ed.). The Condensed Chemical Dictionary, 8th ed.
New York, Van Nostrand Reinhold Co. 1971.
Newsome, W. H., J. B. Shields, and D. C. Villeneuve. Residues of
maneb, ethylenethiuram monosulfide, ethylenethiourea, and ethyl-
enediamine on beans and tomatoes field treated with maneb. J.
Agr. Food Chem. 23_(4) : 756-758, 1975.
NIOSH. Registry of Toxic Effects of Chemical Substances. 1977.
North American Contact Dermatitis Group. The frequency of con-
tact sensitivity in North America 1972-74. Contact Dermatitis
1:277-280, 1975.
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some informa-
tion is not possible. The environmental release data were taken
from NSF/Rann Research Program on Hazard Priority Ranking of
Manufacturing Chemicals.
133
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Petrozzi, J. W., and R. N. Shore. Generalized exfoliative derma-
titis from ethylenediamine. Arch. Dermatol. 112;525-526, 1976.
Provost, T. T., and 0. P. Jillson. Ethylenediamine contact
dermatitis. Arch. Dermatol. £6:231-234, 1967.
SRI (Stanford Research Institute). Directory of Chemical Pro-
ducers. Menlo Park, Calif. 1978.
Van Hecke, E. Ethylenediamine sensitivity from exposure to epoxy
resin hardeners and Mycolog cream. Contact Dermatitis 1^:344-348,
1975.
Wiithrich, B. Occupational eczema due to ethylenediamine in the
synthetic fiber manufacturing industry. Berufs-Dermatosen
20(4):200-203, 1972. (As stated in Biol. Abstr.)
134
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CHEMICAL HAZARD INFORMATION PROFILE
Hexachlorocyclopentadiene
Date of report: March 15, 1977
This chemical was chosen for study because of its
detection in air, water, and fish samples.
The following recommendations are made regarding further
OTE evaluation of the possible health or environmental
hazards of hexachlorocyclopentadiene (HCCPD):
(1) Check TSCA inventory for production volume—
Reliable production information is not currently
available.
(2) Wait for hazard assessment document from ORNL—
Further OTS assessment at this point would simply
be duplicative of ORNL's effort.
(3) Update this Chemical Hazard Information Profile
based upon the additional information obtained.*
(4) Refer to Office of Solid Waste—HCCPD has been
identified as a waste by-product of pesticide
manufacture.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Hexachlorocyclopentadiene (HCCPD) is a dense, oily,
slightly water-soluble liquid used commercially as an intermediate.
Only two companies produce HCCPD in the United States:
Hooker Chemical Co. at Montague, Mich., and Niagara Falls,
N.Y., and Velsicol Chemical Corp. at Memphis, Tenn. (SRI,
1978). Hooker sells HCCPD as C-56 ; it is occasionally
referred to in the literature as "hex."
'Subsequent to the review of this CHIP document and the
selection of the tentative dispositions given above, the
TSCA Interagency Testing Committee recommended hexachloro-
cyclopentadiene for priority consideration under Section
4(a) of TSCA (44 F.R. 31866).
135
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The important products derived from HCCPD (via Diels-Alder
reactions) are the chlorinated cyclodiene insecticides aldrin,
dieldrin, endrin, chlordane, heptachlor, endosulfan, KeponeS), and
mirex; the fire-retardant monomers chlorendic acid (CA) and
chlorendic anhydride (CAN), used primarily in polyester resins
for marine, automotive, and construction applications, and to a
lesser extent in alkyd resin coatings; and the fire-retardant
plastic additives known as Dechloranes®. (In the past, Dechlo-
rane® was the trade name under which mirex was sold for use as a
fire-retardant additive.) The insecticide dienochlor is also
derived from HCCPD, but via catalytic reduction, rather than a
Diels-Alder reaction. The chemical structures of HCCPD and these
derivatives are shown in the appendix.
Production and Use
Because there are but two producers of HCCPD, production
statistics are not public information. Lu et al. (1975) stated
that production of HCCPD could not be less than 50 million Ib per
year, based on production levels of the chlorinated insecticides
for the early 1970's. This estimate, however, preceded EPA
actions taken against most of these insecticides, which have
severely limited their allowable applications. Within the past 2
years aldrin and dieldrin have had their registrations canceled,
chlordane and heptachlor have had their registrations suspended,
and endrin and Kepone© have been presumed against. Limited,
specific uses of aldrin/dieldrin and chlordane/heptachlor are
permitted under their respective cancellation and suspension
orders. The current mirex formulation is to be phased out by
1978 and replaced by a new formulation. Dienochlor and endosul-
fan have not had any action taken against them to date.
The chlorendic acid/chlorendic anhydride outlet for HCCPD is
a significant market. An estimated 10 million Ib of CA/CAN was
produced in 1974, and the expected growth rate is 10%/year
through 1980 (SRI, 1976). Production of 10 million Ib of CA/CAN
requires 7-7.5 million Ib of HCCPD. These compounds are also
produced only by Hooker and Velsicol.
The production levels of the Dechlorane® fire retardants are
unknown. Dechlorane fire retardants are Hooker products.
Based on the above, HCCPD production at this time is at
least 7 million Ib per year and is substantially less than 50
million Ib per year. Using data on current production capacities
of dienochlor and endosulfan, allowing for some small production
of the canceled and suspended insecticides for their few allowable
uses, and assuming that Dechlorane©fire-retardant production is
on the order of 1 million Ib per year, an upper limit on current
HCCPD production of 15 million Ib per year can be assumed.
136
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Health Aspects
The toxicological hazards (particularly carcinogenicity),
persistence, and widespread environmental contamination with
certain of the HCCPD-derived insecticides are well known (IARC,
1974) , and these features have formed the basis of the restric-
tive actions that have been taken against them. Very little is
known about the health and environmental effects of HCCPD, and
the available information on CA/CAN and the Dechlorane^' materials
is practically nonexistent.
HCCPD produces systemic toxicity of unknown mechanism in
mammals via ingestion, inhalation, and dermal exposure. Degener-
ative changes in the brain, heart, adrenals, liver, kidneys, and
lungs are observed in severely poisoned animals by all routes of
administration. The oral LDsg in rats is 500-600 mg/kg. Rats
receiving 30, 100, or 300 ppm HCCPD in their diets did not show
any abnormalities after 90 days. Rats fed 0.002, 0.0002, or
0.00002 mg/kg daily for 6 months showed no abnormalities. The
minimum lethal dose of HCCPD applied to rabbit skin is 430-610
mg/kg. Rats, rabbits, and guinea pigs survived 150 7-hr expo-
sures to 0.15 ppm HCCPD in the air over a 216-day period; how-
ever, this exposure level was lethal to four of five mice. All
species showed mild degenerative changes in the liver and kid-
neys. Most animals in all four of these species died from a
single 7-hr exposure to 3.2 ppm HCCPD in the air (Ingle, 1953;
Treon et al., 1955; Naishstein and Lisovskaya, 1965).
No data are available on the carcinogenicity, mutagenicity,
or teratogenicity of HCCPD.
For aquatic species, the reported 96-hr TLM's are 25 ppm for
sunfish, 20 ppm for bass, and 0.059 ppm for fathead minnows
(Davis and Hardcastle, 1959; U.S. DHEW, 1956).
A model ecosystem study showed that HCCPD has considerable
ecological stability and moderate biomagnification potential in
aquatic organisms (Lu et al., 1975).
HCCPD has been qualitatively identified as a contaminant in
the discharge of a pesticide production plant (probably Velsicol)
in Memphis, Tenn., on seven occasions, most recently in December
1975 (Donaldson, 1977). This past May at the Hooker plant in
Michigan, HCCPD was qualitatively identified in air, in the
plant's aqueous discharge (56 ppb; 170 ppb), and in fish tissue
in the receiving stream (4-18 ppb). According to Dennis Swanson
of the Michigan State Department of Natural Resources, Hooker has
agreed to limit the HCCPD in its aqueous discharge to 10 ppt
(limit of detection).
137
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The only effects information available for CA/CAN is an LDso
value of 0.5 g/kg for CAN given to rats via stomach tube (Kowalski
and Bassendowska, 1965). No reports of environmental contamina-
tion with CA/CAN were found.
Environmental Aspects
No information was found in the sources consulted on the
environmental fate or effects of HCCPD.
REFERENCES
Davis, J. T., and W. S. Hardcastle. Biological assay of herbi-
cides for fish toxicity. Weeds 7^:397-404, 1959.
Donaldson, W. Analytical Chemistry Branch, Environmental Research
Laboratory, Athens, Ga., private communication, 1977.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Man: Some Organochlorine Pesticides (vol. 5). 1974.
Ingle, L. Toxicity of chlordane vapors. Science 118; 213-214,
1953.
Kowalski, Z., and E. Bassendowska. Acute toxicity of phthalates
used in the plastic industry. Med. Pr. 16> (2): 109-112, 1965.
Lu, P., R. L. Metcalf, A. S. Hirive, and J. W. Williams. Evalua-
tion of environmental distribution and fate of hexachlorocyclo-
pentadiene, chlordene,.heptachlor, and heptachlorepoxide in a
laboratory model ecosystem. J. Agr. Food Chem. 23(5):967-973,
1975.
Naishstein, S. Ya., and E. V. Lisovskaya. Maximum permissible
concentration of hexachlorocyclopentadiene in water bodies. Gig.
Sanit. 3_0j117-181/ 1965.
SRI (Stanford Research Institute). Chemical Economics Handbook
(Unsaturated Polyester Resins; Maleic Anhydride). Menlo Park,
Calif. 1976.
SRI. Directory of Chemical Producers, United States of America.
Menlo Park, Calif. 1978.
Treon, C., F. Cleveland, and J. Cappel. The toxicity of hexa-
chlorocyclopentadiene. Arch. Ind. Health _11_: 459-472, 1955.
U.S. Department of Health, Education, and Welfare (DHEW). Bio-
Assay Investigations for International Joint Commission. Hooker
Electrochemical Co., Niagara Falls, N.Y. 1956.
138
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APPENDIX. Chemical Structures
Cl
H exach lorocyc lopentad iene
(HCCPD)
COOH
Chlorendic Acid
(CA)
Cl
Chlorendic Anhydride
(CAN)
75-90%
Cl
5-24%
Br3 1-5%
Dechlorane 604
®
139
-------
APPENDIX (Continued)
cr ^y^ ^ ' ^f ci
Cl CI
Dechlorane 25
Dechlorane 515 (same structure,
different particle size)
Cl
A*
C'S Cl
W"
Cl
VCI
Mi rex (was formerly
Dechlorane as well)
Cl
Cl
Endrin
Cl
140
-------
APPENDIX (Continued)
Cl
Cl
Cl
Cl
Cl
Cl
Endosulfan
Cl.
Cl
.Cl
Cl
Cl
Cl
"Cl
Kepone
.®
Cl Cl Cl Cl
Dienochlor
141
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CHEMICAL HAZARD INFORMATION PROFILE
HexamethyIphosphoramide
Date of report: August 1976
This chemical was chosen for study because of a report that
hexamethylphosphoramide (HMPA) induced squamous cell carcinoma in
rats. It is recommended that this report be referred to the
Office of Solid Waste. HMPA has been found in the waste products
from certain industrial processes. It is also recommended that
8(a) information be obtained to better define the exposure poten-
tial of HMPA. This report will be revised in light of the 8(a)
information.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may not reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
This report with attachments was prepared for the purpose of
organizing the available information on the chemical hexamethyl-
phosphoramide (HMPA) and to review the developments during the
period September 1975 through August 1976 regarding this poten-
tially hazardous substance.
On September 24, 1975, Dr. C. F. Reinhardt of E. I. du Font's
Haskell Laboratory notified NIOSH that HMPA induced squamous cell
carcinoma of the nasal cavity in rats inhaling 400 to 4,000 ppb
(by volume) of the material for 6 hr per day, 5 days per week for
8 months (Attachment I). Although no cancerous lesions were
observed in rats exposed to 50 ppb at the end of 8 months, a
subsequent report noted the same effect at this level beginning
after 13 months of exposure (Attachment II). The Office of Toxic
Substances was notified of this finding on October 1, 1975, and
undertook a quick survey of the available information on HMPA to
determine its current uses, potential for environmental release,
and other toxicological features. A brief memo dated October 10,
1975, was prepared by the Early Warning Branch (Attachment III).
A more detailed report was prepared by NIOSH, dated October 24,
1975, which concentrated on potential occupational exposure to
HMPA (Attachment IV).
142
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The significant information developed in these initial
studies is the following. HMPA is known to be produced in the
United States by du Pont at Deepwater, N.J.; Chemical Samples Co.
at Cleveland, Ohio; and Fike Chemical Co. at Nitro, W. Va.
Du Pont does not sell HMPA, but ships it to their Spruance, Va.,
plant for use in the production of its Kevlar© polyaramid pro-
duct. The other two companies sell HMPA, and both domestic and
some imported HMPA is distributed by about 11 other companies.
The quantity of HMPA produced and sold annually is unknown.
HMPA is used as a solvent in research laboratories and,
according to the NIOSH report, this constitutes the major source
of occupational exposure. HMPA has been studied for its activity
as an insect chemosterilant, but it is not used commercially as
such. HMPA has also been studied for use in PVC resins as a UV
light inhibitor, as a jet fuel deicing agent, as a flame retard-
ant, and as an antistatic agent (Merck Index, 1968). The only
known commercial use of HMPA appears to be as a speciality
solvent by du Pont for the manufacture of the Kevlar® product as
mentioned above. According to du Pont, the finished Kevlar©
product contains less than 1 ppm HMPA by weight which is bound
firmly to the fiber. It is du Font's belief that this does not
pose a hazard to persons handling the finished Kevlar4£ fiber
(Attachment I).
Very little additional data on the biological effects of
HMPA was found. LDso values range from 2,500-3,500 mg/kg in rats
exposed orally, cutaneously, or intradermally; 2,600 mg/kg in
rabbits exposed cutaneously; and 835 mg/kg in chickens exposed
orally (NIOSH, 1975). Acute systemic toxicity includes altera-
tions in the renal, gastrointestinal, and nervous systems (Kim-
brough and Gaines, 1966; Kimbrough and Sedlack, 1968; Shott et
al., 1971). Inhaled HMPA enhances chronic murine pneumonia in
rats (Overcash,.1973). HMPA is a mutagen for fruit flies (Benes
and Sram, 1969). Studies on human (Chang and Klassen, 1968) and
mouse (Manna and Das, 1973) chromosomes revealed no increased
frequency of HMPA-induced chromosomal aberrations compared to
controls. Testicular atrophy and aspermia have been noted in
rats receiving HMPA orally (Jackson et al., 1970). HMPA also
inhibits testicular development in orally dosed cockerels (Sher-
man and Herrick, 1970).
NIOSH estimated that 5,000 persons are occupationally
exposed to HMPA, of which more than 90% involve exposure in
research laboratories (Attachment IV). Except for the possible
exposure through residual HMPA in Kevlar®, no nonoccupational
human exposure was identified.
No data were available in 1975 on levels of HMPA in environ-
mental samples, nor on the persistence, bioaccumulation potential,
or other possible effects of HMPA as an environmental contaminant.
143
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Because of the limited production and the use pattern of HMPA,
widespread environmental contamination did not appear likely, and
the focus of concern remained on occupational exposures.
In April 1976, du Pont supplied data to EPA Region III
regarding levels of HMPA in the liquid discharge of the Spruance,
Va. , plant into the James River during January-March 1976 and the
levels of HMPA in the atmosphere within and around this same
plant (Attachment V) . These data indicated that 48 Ib of HMPA
was being discharged daily into the James River during January,
63 Ib per day during February, and 22 Ib per day during March.
Measurements in the James River below the plant discharge site
showed levels of HMPA at about 0.5 ppb, the lower limit of
detectability. Some limited data were also supplied on the acute
effects of HMPA to aquatic life. Using 96-hr static, unaerated
conditions, the LCso °^ HMPA was found to be 7,500 ppm for blue-
gill sunfish and 6,495 ppm for Daphnia magna. Outside air con-
centrations of HMPA were below 0.05 ppb (limit of detection) in
samples taken within the confines of the plant and in off-plant
locations (0.5 to 1 mile distant). Air concentrations within the
operating areas of the plant were below 0.5 ppb, except for small
regulated areas where concentrations up to 50 ppb were observed.
Personnel in these latter areas are required to use respirators.
In the same report, du Pont described improvements in con-
trol equipment and procedures at the Spruance plant to reduce
HMPA losses to the environment in air, in water, and through
solid waste disposal. These improvements include elimination or
control of HMPA leaks in process equipment, relocation of primary
exhaust to a high-elevation stack, incorporation of activated
carbon to remove HMPA from liquid waste streams, and incineration
of Kevlar(jy process solid wastes on-site and through a disposal
contractor. Prior to this, the solid wastes were apparently not
incinerated, but were stored in drums on a private land disposal
site near Anniston, Ala.
In early 1976, there was some concern that the storage of
Kevlar^j solid wastes at the Anniston site might result in HMPA
contamination of local drinking water (Attachment VI) . EPA
Region IV, together with du Pont, investigated the site where
about 5,000 steel and cardboard drums representing several years
worth of Kevlar® process waste were being stored. The material
in the drums consisted of about 80% sulfuric acid and 20% inert
polymers, with about 20-30 ppm HMPA present initially. The HMPA
supposedly would break down in the sulfuric acid to phosphoric
acid and phosphate salts. Some of the containers had corroded,
and because of the presence of a well on the disposal site and
general runoff considerations, contamination of water systems
could have occurred. Detectable levels of HMPA were found in the
water and sediment of a drainage ditch downstream from the dis-
posal site, in the well at the disposal site, and in a private
144
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well upgrade from the disposal site. No HMPA was detected in the
raw or finished drinking water of Anniston. Du Pont agreed to
remove the drums from the site and have the contents incinerated;
EPA planned to lime the disposal site and seal the on-site well.
Overall, the HMPA problem appears to be receiving adequate
attention both by industry and the concerned Government agencies.
As indicated by the information developed initially, the major
focus of concern over HMPA remains with occupationally exposed
individuals, and no intensive study of HMPA as a critical envi-
ronmental problem by the Office of Toxic Substances is warranted.
The Office of Toxic Substances will retain an up-to-date file on
HMPA to facilitate rapid response to any future developments. As
suggested in the October 10, 1975, Early Warning Branch memo
(Attachment III) , information on the production and uses of com-
pounds chemically related to HMPA has been developed. This
package (Attachment VII) is now under review by the Early Warning
Branch.
REFERENCES
Benes, V. , and R. J. Sram. Mutagenic activity of some pesticides
in Drosphila melanogaster. Ind. Med. Surg. 3^(12) : 442-444, 1969.
Chang, T. H. , and W. Klassen. Comparative effects of tretamine,
tepa, apholate, and their structural analogs on human chromo-
somes in vitro. Chromasoma ^4_(3) : 314-323, 1968.
Jackson, H. , A. R. Jones, and E. R. A. Cooper. Effects of hexa-
methylphosphoramide on rat spermatogenesis and fertility. J.
Reprod. pert. 20^263-269, 1970.
Kimbrough, R. D. , and J. B. Gaines. Toxicity of hexamethylphos-
phoramide in rats. Nature 211:146-147, 1966.
Kimbrough, R. D. , and V. A. Sedlack. Lung morphology in rats
treated with hexamethylphosphoramide. Toxicol. Appl. Pharmacol.
:60-67, 1968.
Manna, G. K. , and P. K. Das. Effect of two chemosterilants,
apholate and hempa, on the bone-marrow chromosomes of mice. Can.
J. Genet. Cytol. 15_(3) : 451-459, 1973.
The Merck Index, 8th ed. Rahway, N.J., Merck and Co. 1968. p.
528.
NIOSH. Registry of Toxic Effects of Chemical Substances. 1975.
p. 903.
Overcash, R. G. Enhancement of natural and experimental chronic
respiratory disease in the rat by oral hexamethylphosphoramide.
Z. Rechtsmed. 1973.
145
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Sherman, M., and R. B. Herrick. Acute toxicity of five insect
chemosterilants, hemel, hempa, tepa, metepa, and methotrexate,
for cockerels. Toxicol. Appl. Pharmacol. 16_: 100-107, 1970.
Shott, L. D., A. B. Borkovek, and W. A. Knapp. Toxicology of
hexamethylphosphoric triamide in rats and rabbits. Toxicol.
Appl. Pharmacol. 1£(13):499-506, 1971.
ATTACHMENTS*
I. Letter from Dr. C. F. Reinhardt, Haskell Laboratory for
Toxicology and Medicine, E. I. du Pont and Co., to Dr. John
Finklea, Director, NIOSH, September 24, 1975.
II. Two-Year Inhalation Toxicity Study on HexamethyIphosphoramide
(HMPA): One Year Interim Report, H. J. Trochimowicz, J. W.
Sarver, K. P. Lee, and S. P. Shrivastava (Haskell Laboratory
for Toxicology and Medicine, E. I. du Pont and Co.), pre-
sented at the American Industrial Hygiene Association Meeting,
May 19, 1976, Atlanta, Ga.
III. "Hexamethyl phosphoramide (HMPA)," memo from Frank Letkiewicz
to Dr. Farley Fisher, Chief, Early Warning Branch, OTS,
October 10, 1975.
IV. Background Information on Hexamethylphosphoric Triamide,
Office of Occupational Surveillance and Biometrics, NIOSH,
October 24, 1975.
V. Letters from Mr. Howard Kress, plant manager, Spruance plant,
du Pont, to Mr. Ralph Rhodes, Toxic Substance Coordinator,
EPA Region III, April 14, 1976; April 30, 1976.
VI. (a) "Disposal of Hazardous Waste In and Near Anniston,
Alabama," memo from Elmer Cleveland, EPA Region IV, to
the Record, May 17, 1976.
(b) "Investigation of Possible Environmental Damage from
'Kevlar1 Waste Products Stored Near Anniston, Alabama,"
memo from William Davis, EPA Region IV, to James Fringer,
Director, Surveillance and Analysis Division, EP£ Region
IV, May 17, 1976.
(c) Letter from M. D. Lair, Chief, Engineering Section,
Water Surveillance Branch, EPA Region IV, to Mr. Robert
Spenser, E. I. du Pont de Nemours and Co., Inc., June 4,
1976.
VII. Compilation of Information on Chemicals Structurally Related
to HMPA, prepared by Tracor-Jitco, Inc., under contract 68-
01-3255, Task #8.
*Attachments I-VII are available in the OPTS public reading room
located in Room E447 at EPA Headquarters.
146
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CHEMICAL HAZARD INFORMATION PROFILE
n-Hexane
Date of report: May 13, 1977
This chemical was chosen for study because of its reported
involvement in occupational polyneuropathies.
The following recommendations are made regarding further OTE
evaluation of the possible health or environmental hazards of n-
hexane:
(1) Defer to the actions of NIOSH and OSHA—Possible occu-
pational problems will be addressed in a NIOSH Criteria
Document.
(2) Transmit this report to OAQPS—Atmospheric losses of n-
hexane may cause significant local exposures.
(3) Transmit this report to CPSC—n-Hexane may be used as a
solvent in consumer products such as glues and cleaning
fluids.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may not reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Chemical Identity
n-Hexane is a saturated straight-chain hydrocarbon with the
molecular formula CgH-jj* At room temperature n-hexane is a
colorless, very volatile liquid (boiling point, 69°C) with a
faint, peculiar odor. n-Hexane is insoluble in water but fairly
soluble in organic solvents (alcohol, ether, and chloroform)
(Merck Index, 1976).
Production and Use
The three most commonly used charge stocks for the produc-
tion of commercial hexanes are straight-run gasoline, the higher
boiling portion of the liquid product stripped from natural gas,
and a refinery stream known as "BTX raffinate" (the paraffinic
portion that remains after the removal of benzene, toluene, and
xylene from a naphtha which has been refined to convert naph-
thalenes to aromatics). Two basic methods are used in the
147
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manufacture of n-hexane from these three stocks. One involves
the close fractionation of feedstocks which separates n-hexane on
the basis of boiling point. The second, more recently developed
method of production uses adsorption on "molecular sieves" to
separate the hexane product from the crude stocks. A molecular
sieve is an adsorbent material of closely controlled pore size
which allows normal paraffins to pass into the pores and be
adsorbed while rejecting branched-chain paraffins, naphthenes,
and aromatics. Molecular sieve separation permits the manufac-
turer to produce a hexane product of almost any desired n-hexane
composition through adjustments in the operating cycle. The
composition of fractionated hexanes, on the other hand, depends
on the constitution of the charge stocks and thus offers the
producer much less leeway in final product selection (Porter,
1964).
The compositions of three typical commercial hexanes are
listed in Table 1. These examples illustrate the wide range of
hydrocarbon distribution and minor impurity content that may be
encountered in commercial products. Hexanes of many different
combinations of components are the norm for the market (Porter,
1964).
Annual production of n-hexane is estimated at four billion
pounds (EPA, 1979).
The chief commercial uses of hexane are as a solvent for the
extraction of oil seeds, a reaction medium, and a component in
the formulation of various products. Extraction of oil seeds is
the single largest volume use of hexane. Hexane is the solvent
of choice for this purpose because of its high solvency for seed
oil, the low boiling point of the solvent, giving easy separation
of hexane from the oil and meal, and also hexane's low toxicity
and cost. A narrow boiling hexane is required to hold down
solvent losses during separation, and low benzene content is
necessary to minimize toxicity (Porter, 1964).
Hexane is used in the extraction of the following oil seeds:
soybeans, cottonseed, flaxseed, safflower seed, corn germ, peanuts,
and several other smaller volume seeds. Soybeans and cottonseed
represent the greatest extraction volume based on hexane (Porter,
1964).
Hexane is used extensively as a reaction medium in the pro-
duction of polyolefins, certain elastomers, and Pharmaceuticals.
Examples of the first two categories are polypropylene, poly-
isopropene, high-density polyethylene, and ethylene-propylene
rubber. The solvent serves as a catalyst carrier and at times
acts to control final product molecular weight by dropping the
polymer out of solution when a certain molecular size is attained.
Hexane for this use must be relatively pure or the reaction may
be adversely affected (Porter, 1964).
148
-------
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The third major use of hexane is as a product component.
Hexane is found in quick-drying cements, certain two-solvent-
system adhesives (controls viscosity and reduces drying time),
and some lacquers and printing inks where a quick drying diluent
is desired (Porter, 1964).
Health Aspects
The acute toxicity of n-hexane is primarily that of a local
irritant and, in larger doses, a CNS depressant with symptoms
such as dizziness, numbness in extremities, and difficulty in
walking (ITII, 1976; Herskowitz et al., 1971). Chronic exposure
to n-hexane concentrations of approximately 500 ppm for several
months can lead to progressive peripheral nervous system involve-
ments in a dose-related manner. Polyneuropathy begins insidi-
ously 2-6 months (or longer, depending on the individual and the
level of exposure) after exposure to n-hexane commences, and
continues for 2-3 months after exposure has ceased. The poly-
neuropathy can be either sensory of the "glove and stocking" type
or sensorimotor with or without muscle atrophy. Slight optic
nerve involvement may occur, but there are no indications of CNS
lesions (Shirabe et al., 1974). Severe cases may exhibit per-
ipheral nervous system demyelination and axonal degeneration,
denervation of muscles, and slow clinical recovery. Recovery,
however, does occur and is generally complete except in very
severe instances where permanent neurological damage can result
(Herskowitz et al., 1971).
Human
There are many documented cases of deleterious effects from
n-hexane exposure in industrial situations.
Three New York cabinet finishers were exposed by oral,
inhalation, and dermal means to an open vat of an n-hexane-
containing solvent. Average n-hexane levels in the air were 650
ppm, with peaks at 1,300 ppm. The workers all developed poly-
neuropathy after a few months exposure but recovered completely
when n-hexane exposure ceased (Herskowitz et al., 1971).
Paulson and Waylonis (1976) reported a study concerning a
printing plant where at least 8 of 50 total workers exposed to n-
hexane developed a mild and recurrent neuropathy with no CNS
involvement. The plant produced a printed paper product with an
adhesive backing; n-hexane was released by the drying adhesive.
n-Hexane levels peaked at 4,060 mg/m^ (1,150 ppm) in portions of
the plant. The study covered 25 years.
Abbritti et al. (1976) postulated that nearly 400 cases of
polyneuropathy between 1957 and 1973 formerly attributed to TOCP,
as well as 122 newly documented cases of polyneuropathy in the
150
-------
Italian shoe industry, were actually due to C5 and Cg alkane
exposure. Chemical analysis of glues and cleaning fluids used in
several factories with incidents of polyneuropathy showed the
presence of low-boiling paraffinic hydrocarbons (n-hexane,
pentane, 2-raethylpentane, 3-methylpentane, etc.) in concentra-
tions of over 80% by weight.
Two leather factory workers developed polyneuropathy follow-
ing exposure to an n-hexane-containing glue. Tests on the factory
air showed a total "solvent" level greater than 500 ppm. n- ;
Hexane was not positively identified as the causative agent, but
likely contributed to the difficulty (Assouly et al. , 1972).
Four cases of polyneuropathy in Japan were linked to an n-
hexane containing solvent used in a printing process (Yoshida et
al., 1974).
Yamamura (1969) reported 93 cases of polyneuropathy in the
Japanese sandal industry. A rubber adhesive was the source of
the n-hexane, and air concentrations between 500 and 2,500 ppm
were found. There were several severe cases, with some indi-
viduals displaying cranial neuropathy and permanent damage.
There are many documented cases of n-hexane induced poly-
neuropathy following deliberate chronic glue sniffing (Altenkirch
and Mager, 1976; Shirabe et al. , 1974; Asbury et al. , 1974).
Laboratory Animals
Several experiments dealing with the effects of n-hexane on
lab animals were located and have been summarized.
Kimura et al. (1971) reported the (acute) oral LD5Q values
for undiluted n-hexane in rats of various ages. n-Hexane was
significantly more toxic in the youngest group (14 days old) ,
producing an oral LD5Q (ml/kg) of 24.0 as compared with the two
older groups producing an LD5Q of 49.0 in the young adults and an
of 43.5 in the older adults (Kimura et al., 1971).
Bohlen et al. (1973) explored the kinetics of uptake and
distribution of n-hexane in rat tissue following exposure to an
atmosphere containing approximately 5% n-hexane. The blood,
brain, adrenals, kidneys, and spleen attained a saturation value
within 4-5 hr. The liver n-hexane concentration, however,
increased linearly with exposure and did not reach saturation
within 10 hr. This observation was explained on the basis of an
n-hexane induced accumulation of triglycerides in the liver. A
correlation was established between the value of the hexane
saturation point and the total lipid content of each organ.
151
-------
Truhaut et al. (1973) found that rats exposed for 5-6 months
to an atmosphere containing 2,000 ppm hexane developed various
neurological difficulties. Electrophysical measurements showed
decreased conduction velocity, increased refractory period, and
decreased excitability. Histological examination revealed
demyelination.
Bonashevskaya and Partsef (1971) explored the effects on
rats of "expected" urban atmospheric levels of mixtures of equal
parts of n-hexane and pentane ranging from 3.0-94.7 mg/m^ (0.8-
26.3 ppm). The rats receiving the higher concentrations were
significantly affected in a dose-related manner. Observed damage
included structural changes in the cerebral cortex, alterations
in the motor chronaxy of muscle antagonists (less excitable), and
injury to apical dendrites of neurons. The lowest exposure group
(3.0 mg/m ) was unaffected. All groups were exposed for 2 months.
Kramer et al. (1974) demonstrated that n-hexane is rapidly
hydroxylated in mice by the liver. DiVincenzo et al. (1976)
identified these metabolites as 5-hydroxy-2-hexanone and 2,5-
hexanedione in guinea pigs. These n-hexane metabolites were
identical to those found following methyl-n-butyl ketone (MnBK)
exposure in guinea pigs, which suggests that a common metabolic
pathway may exist for the neuropathy. MnBK was implicated in
several cases of peripheral neuropathy affecting factory workers
in a plastic coating-printing plant. The neurological pattern
was that of a distal, motor, and sensory disorder with minimal
reflex loss. The onset of the condition was invariably insidi-
ous. The authors noted the similarity between the effects of
hexane and MnBK and attributed this to the possible biotransfor-
mation of each to the same active metabolite (Abdel-Rahman et
al., 1976). 2,5-Hexanedione, when administered as such to rats,
produced varying degrees of peripheral neuropathy in that species
also (Raleigh et al., 1975; Spencer and Schaumburg, 1975).
Foa et al. (1976) showed that n-hexane alone had no neuro-
logical effect on pigeons when administered by inhalation or
percutaneous means (8% pure n-hexane in an inhalation chamber for
5 hr/day, 5 days/week for 17 weeks; a second group received
approximately the same dose for the same period of time by per-
cutaneous means). No clinically discernible alterations of the
nervous system were noted at the experiment's conclusion. Subse-
quent neurophysiological and histopathological examinations also
revealed no noticeable alterations of the nervous system. The
conclusion reached was that n-hexane can only induce neurological
change when in combination with other solvents (if n-hexane is
involved at all). These results have not been corroborated.
Hexane lethality in rats is modified by changes in environ-
mental temperature. An increase from 26° to 36°C decreased the
152
-------
lethal dose from 9,100 to 530 mg/kg. Conversely, temperature
depression increased the lethal dose to 4/000 mg/kg at 8°C (Kep-
linger et al., 1959).
Environmental Aspects
The following are brief descriptions of the most pertinent
environmental concerns associated with n-hexane.
Oil Seed Extraction Losses
The loss of n-hexane from oil seed extraction facilities may
represent a serious local problem. Porter (1964) estimated that
atmospheric losses of n-hexane in "modern" soybean extraction
plants generally run between 0.5 and 1.0 gallon of n-hexane per
ton of soybeans extracted; losses at older plants are expected to
be greater. Using Porter's (1964) figures, the daily loss will
be 600 gallons or 2.2 (105) gallons annually.
The n-hexane emissions from other types of oil seed extrac-
tion facilities are not known, although Porter (1964) reports
that solvent losses from cottonseed and flaxseed extraction sites
generally exceed those encountered at soybean plants.
Localized release of these large amounts of n-hexane may
represent a very real health hazard, especially in terms of
chronic exposure (for which there are no available toxicity
data).
Mobile Source Emissions
Hydrocarbons emitted from all mobile sources were estimated
to equal 13.8 million tons per year in 1970. n-Hexane was esti-
mated to represent 1.2 volume percent of total emitted hydrocar-
bons .(equivalent to roughly 0.17 million tons of hexane) . This
percentage was expected to decrease after 1972 because of the
mandatory use of catalytic converters on some passenger cars
(CUT, 1977) .
Losses from the Synthetic Elastomer Industry
n-Hexane is one of many solvents (others include pentane,
heptane, benzene, cyclohexane, chlorobenzene, etc.) used in the
synthetic elastomer industry as the reaction medium in both the
solution and emulsion procedures. The magnitude of the solvent
losses expected from this industry is difficult to assess. There
are a number of opportunities for solvent escape: during produc-
tion of the elastomer; while stripping the solvent from the
finished product; and various fugitive losses occurring during
the storage and pumping of the solvent.
153
-------
Given the great production volume of the synthetic elastomer
industry, the potential for environmental abuse arising from
solvent release may be an appreciable problem in the locale of
the plant sites. The loss of solvents other than n-hexane may
prove more of a problem given the greater demonstrated toxicity
of several of the listed solvents. The scope of the problem,
however, remains ill defined owing to the paucity of available
information.
Other Considerations
n-Hexane, like other vapor-phase organic pollutants of
hydrocarbon origin, produces no pronounced effect on the physical
properties of the atmosphere, does not decrease visibility or
affect the amount of solar radiation, and does riot alter precipi-
tation patterns. The possibility that n-hexane, as a relatively
nonreactive paraffin, enters into the photochemical reaction
leading to the formation of peroxyacetylnitrate (PAN) has not
been reported. However, hydrocarbons similar to n-hexane (n-
pentane and methyl pentane) have been implicated in PAN formation
(NAS, 1976).
NOTE: 500 ppm n-hexane equals approximately 1,800 mg/m (ACGIH,
1971).
REFERENCES
Abbritti, G. et al. Shoe-makers' polyneuropathy in Italy: The
aetiological problem. Br. J. Ind. Med. 3_3_: 92-99, 1976.
Abdel-Rahman, M. S. et al. Toxicity and metabolism of methyl n-
butyl ketone. Am. Ind. Hyg. Assoc. J. 3J7(2):95, 1976.
ACGIH (American Conference of Governmental Industrial Hygienists).
Documentation of the Threshold Limit Values for Substances in
Workroom Air. 1971.
Altenkirch, H., and J. Mager. Toxic polyneuropathy after sniffing
contact glue thinner. Dtsch. Med. Wochenschr. 101:195-198, 1976.
(Abstract)
Asbury, A. K. et al. Glue sniffing neuropathy. J. Neuropathol.
Exp. Neurol. 3_3^1):99, 1974.
Assouly, M. et al. Polyneuritis caused by n-hexane. Arch. Mai.
Prof. Med. Trav. Secur. Soc. 33J6):309-310, 1972. (Abstract)
Bohlen, Peter et al. Uptake and distribution of hexane in rat
tissues. Toxicol. Appl. Pharmacol. £5_: 242-249, 1973.
154
-------
Bonashevskaya, T. I., and D. P. Partsef. Experimental studies of
the effects of microconcentrations of a mixture of pentane and
hexane in air. Hyg. Sanit. 3_6:339-343, 1971. (Engl. trans.)
CUT (Chemical Industry Institute of Toxicology) . CUT Current
Status Reports, No. 1, n-Hexane. 1977.
Directory of Chemical Producers - U.S.A. Menlo Park, Calif.,
Stanford Research Institute. 1978.
DiVincenzo, G. D. et al. Characterization of the metabolites of
methyl n-butyl ketone, methyl iso-butyl ketone, and methyl ethyl
ketone in guinea pig serum and their clearance. Toxicol. Appl.
Pharmacol. 36; 511-522, 1976.
Foa, V. et al. Experimental n-hexane neurotoxicity. Med. Lav.
67_(2): 136-144, 1976. (Summary)
Herskowitz, Allan, N. Ishii, and Herbert Schaumburg. n-Hexane
neuropathy: A syndrome occurring as a result of industrial
exposure. N. Engl. J. Med. 285(2);82-85, 1971.
ITII (International Technical Information Institute). Toxic and
Hazardous Industrial Chemicals Safety Manual. Tokyo. 1976.
Keplinger, M. L. et al. Effects of environmental temperaure on
the acute toxicity of a number of compounds in rats. Toxicol.
Appl. Pharmacol. !_: 156-161, 1959. (As cited in CUT)
Kimura, Eugene T. et al. Acute toxicity and limits of solvent
residue for sixteen organic solvents. Toxicol. Appl. Pharmacol.
1^:699-704, 1971.
Kramer, A. et al. Effect of n-hexane inhalation on the monooxy-
genase system in mice liver microsomes. Chem-Biol. Interact.
8::11-18, 1974.
Lonneman, W. A. et al. Hydrocarbon composition of urban air
pollution. Environ. Sci. Technol. 8^(3) : 229-236, 1974.
The Merck Index, 9th ed. Rahway, N.J., Merck and Co., Inc.
1976.
NAS (National Academy of Sciences). Vapor-Phase Organic Pol-
lutants, Committee on Medical Biologic Effects of Environmental
Pollutants. 1976. (As cited in CUT)
Paulson, George W., and George W. Waylonis. Polyneuropathy due
to n-hexane. Arch. Intern. Med. 136:880-882, 1976.
155
-------
Porter, C. A. Hexanes. In Kirk-Othmer Encyclopedia of Chemical
Technology, 2nd ed., vol. 11. 1964.
Raleigh, R. et al. Methyl n-butyl ketone. Arch. Environ. Health
3_0:317-318, 1975. (As cited in CUT)
Shirabe, Teruo et al. Toxic polyneuropathy due to glue sniffing.
J. Neurol. Sci. 2^:101-113, 1974.
Spencer, P. S. and H. H. Schaumburg. Experimental neuropathy
produced by 2,5-hexadione - A major metabolite of neurotoxic
industrial solvent methyl n-butyl ketone. J. Neurol. Neurosurg.
Psychiatry 38_(8) : 771-775, 1975. (As cited in CUT)
Truhaut, R. et al. First electrophysiological results after
experimental intoxication with technical hexane and heptane in
the albino rat. Arch. Mai. Prof. 34J7-8):417-426, 1973. (Summary)
U.S. EPA. Toxic Substances Control Act Chemical Substance
Inventory, Office of Pesticides and Toxic Substances, Washington,
D.C. 1979.
U.S. Tariff Commission. Crude Products from Petroleum and
Natural Gas. 1972-75.
Yamamura, U. n-Hexane polyneuropathy. Folia Psychiatr. Neurol.
Jpn. 23^45-57, 1969. (As cited in Paulson and Waylonis and in
Herskowitz et al.)
Yoshida, T. et al. Four cases of n-hexane polyneuropathy and its
electrophysical studies. Clin. Neurol. 14_: 454-461, 1974.
(Abstract)
156
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CHEMICAL HAZARD INFORMATION PROFILE
Isopropyl Alcohol
Date of report: December 29, 1977
Revised : November 20, 1979
This chemical was chosen for study because of reported liver
damage to workers in an isopropyl alcohol packaging plant. It
was subsequently learned that the liver damage was actually due
to isopropyl alcohol's potentiation of carbon tetrachloride
hepatotoxicity.
It is recommended that isopropyl alcohol receive low
priority for further assessment.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and
the environment. The information contained in the report is
drawn chiefly from secondary sources and available reference
documents. Because of the limitations of such sources, it
necessarily follows that this report may not reflect all
available information on the subject chemical.
Any recommendations based on this report are tentative
and should be construed as final Agency policy with respect
to the subject chemical.
Chemical Identity
CH,-CHCH,
3 , 3
OH
Cas No.: 67-63-0
Synonyms: Isopropyl alcohol, 2-propanol, secondary propyl
alcohol, dimethyl carbinol, Perspirit, Petrohol,
Avantine, IPA
Isopropanol, (CH3)2CHOCH,is a colorless liquid with a
pleasant ordor similar to that of an ethanol/acetone mixture.
Its molecular weight is 60.09. The melting point of isopropanol
is -89.5 C; the boiling point is 82.4°C. Isopropanol is
miscible with water, alcohol, ether, and chloroform. Isopropanol
and water form an azeotrope with a boiling point of 80.4 C
(87.7% isopropanol, w/w). The specific gravity of isopropanol
is 0.7863 at 20°C; the vapor pressure is 33 mm Hg (Hawley, 1977).
157
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Health Aspects
NIOSH estimates that approximately 141,000 employees are
potentially exposed to ispropyl alcohol (NIOSH, 1976). OSHA has
set the time-weighted average exposure at 400 ppm (NIOSH, 1977).
Nelson et al. (1943) exposed human subjects to various concentra-
tions of isopropanol to determine what level can be tolerated in
the workplace. The highest concentration which the majority of
the subjects estimated would be satisfactory for an 8-hour expo-
sure was 200 ppm. This is also the level where the subjects
were first able to detect the presence of isopropanol. At 400
ppm there was mild irritation of eyes, nose, and throat, but no
narcosis.
The chemical activity of isopropyl alcohol is primarily
associated with the hydroxyl group. As a secondary alcohol its
reactivity differs in a number of important ways from primary
alchols, for example, in ease of conversion to ethers and
esters, and in the formation of products obtained by oxidation
and catalytic reactions.. It does, however, undergo many of the
reactions typical of the lower molecular weight primary alcohols.
It reacts readily with metals such as sodium and potassium
and it forms halides by reacting with the corresponding halogen
acid.
CH3ChOHCH3 + HX — CH3CHXCH3 + H20
(Kirk-Othmer, 1968).
Processing Methods
Isopropanol is usually made from propylene, a by-product in
the cracking of heavy petroleum hydrocarbons. The addition of
sulfuric acid to propylene forms propyl sulfate which is hydro-
lyzed to isopropanol.
Q rt Q. 13 Cf*\ tJ /"\
O w * fl *\ O^^ * Ji *\ ^tJ
Hf^ — /"•tl /TJ r^ti
v^ — \-.n~ v-»n — "•"•"~ — — — \*+n
heat
OS03H OH
(Morrison and Boyd, 1970) .
Isopropanol is also produced by the catalytic hydrogenation
of acetone.
0 H2
CH.. C - CH7 -------- CH-.CHCH-, (EPA, 1978)
* J catalyst J J
OH
158
-------
Isopropanol is available in three grades: 99%, 95%, and
91% (Hawley, 1977).
Table 1. Major Manufacturers of Isopropanol and Their Production
Levels.
Method of
Production
Company
Locations
Continuous
hydrolysis of
propylene
Catalytic
hydrogenation
of acetone
Solvent-water
azeotropic
distillation
TOTAL
Union Carbide
Corp.
Union Carbide
Corp.
Exxon Corp.
Shell Oil Co.
Union Carbide
Corp.
Shell Oil Co.
ARCO Chemical Co,
Tons/yr.
Charlestown, WV 38,873
Texas City, TX 262,800
Baton Rouge, LA 472,675
Deer Park, TX 299,300
Texas City, TX 195,275
Carson, CA 33,033
Channelview, TX 9,344
Eastman Kodak Co. • Kingsport, TN
73,000
1,384,300
Source: EPA, 1978.
Production and use
Isopropanol is included in many commercial products such as
liniments, lotions, cosmetic, perfumes, hair tonics, permanent
wave preparations, Pharmaceuticals, antifreezes, liquid soaps and
window cleaners. It is used as a preservative in nitrocellulose
lacquer formulations ana dye solutions, as a coupling agent in
oil emulsions, and as an extracting agent for sulfonic acids from
petroleum.oils (Patty, 1963). More than 50% of the isopropanol
manufactured is used as a raw material in the production of
acetone (NIOSH, 1976). It is most popularly known to consumers
as rubbing alcohol, a solution of 70% isopropanol and 30% water.
159
-------
No recorded cases of industrial poisoning by pure isopropyl
alcohol by any route were found in the literature. However,
toxicity due to simultaneous exposure to carbon tetrachloride and
isopropanol has occurred in the workplace. Fourteen workers in
an isopropyl alcohol packaging plant became ill after accidental
exposure to carbon tetrachloride. Renal failure or hepatitis
developed in four cases. Acetone, a product 6f isopropanol *
metabolism, is a major potentiator of carbon tetrachloride
toxicity. Workers had elevated levels of acetone in samples of
expired alveolar gas and were, therefore, predisposed to carbon
tetrachloride injury. Stricter limits for industrial exposure to
CCl. were recommended in cases where isopropyl alcohol is also
found in the work environment (Folland et al., 1976).
Many cases of ingestion of rubbing alcohol have been
reported. This does not seem to be as prevalent as the ingestion
of methanol by chronic alcoholics, but Adelson (1962) reported
five fatal cases that occurred over a seven year period. All
five cases were reported to have consumed approximately 1 pint of
rubbing alcohol. The common symptom of the intoxication was a
deep coma with marked depression leading to an absence of
reflexes. Most acute exposures led to rapid death via central
nervous system depression resulting in respiratory paralysis.
One man lived for 15 days after drinking 1 1/3 pints of rubbing
alcohol. He suffered from ischemic muscular necrosis, upper
gastrointestinal bleeding and kidney failure. He died despite
four episodes of peritoneal dialysis.
Peritoneal dialysis has been recommended to treat acute
isopropanol intoxication especially if hemodialysis is not
available (Dua, 1974). Gleason (1969) reports a case where a
man drank one quart of rubbing alcohol and survived after under-
going hemodialysis.
Isopropanol. is generally considered to be twice as toxic as
ethanol, but less toxic than methanol. Its major metabolite is
acetone (Gleason, 1969;. The symptoms of isopropanol poisoning
follow: 1) Dizziness, incoordination, headache, confusion,
stupor and coria; 2) gastroenteritis with vomiting, hematemesis,
and diarrhea; 3) hypotension, with or without bradycardia, and
sometimes severe circulatory collapse; 4) persistent coma with
hypothermia; 5) death by respiratory arrest; and 6) late
manifestations: aspiration pneumonia; kidney and liver dysfunc-
tion whicn are usually mild and transient by may be serious
(Gleason, 1969).
Wills (1969) ran a study using human subjects to determine
the effects of daily ingestions of small doses of isopropanol.
Groups of 8 men drank a placebo, 2.6 mg/kg or 6.4 mg/kg of
isopropanol daily for 6 weeks. No changes were seen in blood or
urine, optical properties of the eye, or the ability of the liver
to excrete sulfobromophthalein (an indication there was no liver
damage) .
160
-------
There have been a number of cases reported where children
developed comas after topical applications of isopropanol to
reduce high fevers. A 2 1/2 year-old girl was wrapped in a towel
saturated with isopropanol (12 ounces) and a dry towel was placed
over the first. Eight hours later she was limp and totally
unresponsive. This was believed to be caused by inhalation of
isopropanol (Senz, 1958).
Some people have an allergic reaction to skin contact with
isopropanol. The injection site on one woman's arm was cleansed
with an isopropanol swab prior to injection. Subsequently she
held the swab against the site for about 2 minutes. A rash
developed at the injection site and on her fingers. Bullous
lesions developed and had to be drained twice. The condition did
not completely clear up until 21 days later (Wasilewski/ 1968) .
Animal Exposure
The oral LD^Q of isqpropanol in rats, rabbits and dogs is
6-7 gm/kg. By intravenous injection, the anesthetic dose in
rabbits and dogs is 3.3 cc/kg and the fatal dose is 8.2 and 5.1
cc/kg respectively. In a 27 week study, rats were given isopropanol
in their drinking water in solutions ranging from 0.5% to 10%.
Rats refused to drink the 10% solution and died after 7 to 28 days.
The 1% and 5% groups remained well but did experience retardation
of growth and body weight loss (Lehman and Chase, 1944).
Boughton (1944) provided a 5% solution of isopropanol as the
only water supply to a group of rats for nine months. The rats
experienced marked weight depression and noisy breathing, both
of which disappeared after the administration of isopropanol
was stopped. The rats were also sluggish in the maze runs.
There was no difference in the death rate between these rats and
controls. Isopropanol was also applied to the face area of the
rats. After 187 applications of a 50% solution, no injury was
seen-in the skin, hair or eyes.
Carcinogenicity Studies
During the 1940*s, epidemiological evidence raised suspicion
that there was a carcinogen present in the production of isopro-
panol (Weil, 1952). Seven neoplasms of the respiratory tract
were discovered in an isopropanol production unit between 1937
and 1950. Detailed studies of the medical and employment records
of the unit showed that cancer of the respiratory tract developed
in 8.4% of employees exposed for more than five years. Animal
studies on isopropanol and the other chemicals present in the air
of the production unit were conducted to determine which was
responsible for the tumors. Several strains of mice were used for
inhalation and subcutaneous injection experiments. Isopropyl
oil (polypropylene and very small amounts of benzene)
toluene, alkyl benzenes, polyaromatic rings, hexane, acetone,
ethanol, isopropanol, and isopropyl ether, gave positive results
by both subcutaneous injection and mist inhalation. The incidence
161
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of tumors in mice exposed to isopropanol was no different from
that of the controls. The author concludes that isopropanol
is not a carcinogen and isopropyl oil may have been the human
carcinogenic agent in the isopropanol production process.
Environmental Aspects
The BOD of isopropanol is 78% of the theoretical after 20
days at 20°C (total theoretical demand is 2.4 g/g) (Verschueren,
1977). An estimated 50% of isopropanol is eventually dispersed
with an additional 1.5% lost in production. The release rate
would be roughly 876 million I/year if consumption were 1,698
million I/year (Dorigan et al., 1976).
The lethal concentrations of isopropanol to fathead minnows
in Lake Superior waters were determined (EPA, 1976).
LC5Q (mg/1)
1-hr 24-hr 48-hr 72-hr 96-hr
11.830 11,160 11,130 11,30 11,130
Creek chub fish were exposed to isopropanol is Detroit river
water. After 24 hours, no fish died at 90 mg/1 and all fish were
killed by 1,000 mg/1. The 24-hour LC5Q in gold fish is greater
than 5,000 mg/1 (Verschueren, 1977).
Species Inhibition of Cell Toxic Level
Multiplication
Pseudomonas
Putida
(bacteria) 1050 mg/1
Chlorella
Pyrenaidosa 17,000 mg/1
(algae)
Microcystis
aeruginosa 1000 mg/1
(algae)
Brown LC (48 hr) 1400 mg/1
Shrimp LCgX(96 hr) 1150 mg/1
Source: Adapted from Verschueren, 1977.
REFERENCES
Adelson, L. Fatal intoxication with isopropyl alcohol (rubbing
alcohol). Am. J. Clin. Pathol. 38, 144-151, 1962.
Boughton, L.L. The relative toxicity of ethyl and isopropyl
alcohol as determined by long-term rat feeding and external
application. J. Am. Pharm. Assoc. 33, 111-113, 1944.
162
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Dorigan, J. et al. Scoring of Organic Air Pollutants: Chem-
istry, Production, and Toxicity of Selected Organic Chemicals.
MITRE Corp. 1976.*
Dua, S.L. Peritoneal dialysis for isopropyl alcohol poisoning.
J. Am. Med. Assoc. 230(1), 35, 1974.
EPA, Office of Research and Development EPA-600/3-76-097.
Acute toxicity of selected organic compounds to fathead minnows,
1976.
EPA, EPA Guidelines Report, Plants by Product Process, Oct.
1978.
Folland, D.S. et al. Carbon tetrachloride toxicity potentiated
by isopropyl alcohol. J. Am. Med. Assoc. 236(16), 1853, 1976.
Fregert, S. et al. Alcohol dermatitis. Acta Derm. Venereol.
49, 493-497, 1969.
Fuller, H.C. and O.B. Hunter. Isopropyl alcohol - an investiga-
tion of its physiologic properties. J. Lab Clin. Med. 12,
326-349, 1927.
Garrison, R.F. Acute poisoning from use of isopropyl alcohol
in tepid sponging. J. Am. Med. Assoc. 152, 317, 1953.
Gibel, W. et al. (Experimental studies on the carcinogenic
effect of higher alcohols using 3-methyl-l-butanol, 1-propanol
and 2-methyl-l-propanol as examples.) Zeitschrift fur Experi-
mentelle Chirurgie 7(4), 235-239, 1974.
Gleason, M.N. et al. Clinical Toxicology of Commercial Products,
3rd ed. Baltimore, MD, Williams and Wilkins Co., 1969.
Hawley, G.G. (ed.) . Condensed Chemical Dictionary, 9th ed.
New York, Van Nostrand Reinhold Co., 1977.
Hillbom, M.E. et al. Effects of chronic ingestion of some
lower aliphatic alcohols in rats. Research Communications in
Chemical Pathology 9(1), 177, 1974.
Hodge H.C. and W.L. Downs. The approximate oral toxicity in
rats of selected household products. Toxicol. Appl. Pharmacol.
3, 689-695, 1961.
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does
not cite its primary references. Thus, verification of some
information is not possible. The environmental release data
were taken from the NSF/Rann Research Program on Hazard Priority
Ranking of Manufactured Organic Chemicals.
163
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International Technical Information Institute. Toxic and
Hazardous Industrial Chemicals Safety Manual. Tokyo. 1976.
Juncos, L. and J.T. Taguchi. Isopropyl alcohol intoxication -
Report of a case associated with myopathy, renal failure, and
hemolytic anemia. J. Am. Med. Assoc. 204, 732-734, 1968.
June, C.H. Alcoholic ketoacidosis and isopropyl alcohol
intoxication. Arch. Intern. Med. 138, 660, 1978.
Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed., Vol.
16. Anthony Standen, executive editor. New York, John Wiley
and Sons, Inc. 1968.
Lehman, A.J. and H.F. Chase. The acute and chronic toxicity
of isopropyl alcohol. J. Lab Clin. Med 29, 561-567, 1944.
Macht, D.I. Pharmacological Examination of Isopropyl Alcohol,
Arch. Int. Pharmacodyn Ther. 26, 285-289, 1922."
McCord, W.M. et al. Isopropyl alcohol intoxication. South
Med. J. 41, 639, 1948.
McFadden, S.W. and J.E. Haddow. Coma produced by topical
application of isopropanol. Pediatrics 43, 622-623, 1969.
Mclnnes, A. Skin reaction to isopropyl alcohol. Br. Med. J.
1, 357, 1973.
The Merck Index,, 8th ed. Rahway, N.J., Merck and Co., Inc.
1968.
Morris, H.J. and H.D. Lightbody. The toxicity of isopropanol.
J. Ind. Hyg. Toxicol. 20, 428-434, 1938.
Morrison, R.T. and R.N. Boyd. Organic Chemistry, 2nd ed.
Boston, Allyn and Bacon, Inc. 1970.
Nelson, K.W. et al. Sensory response to certain industrial
solvent vapors. J. Ind. Hyg. Toxicol. 25, 282-285, 1943.
NIOSH. Criteria for a recommended standard...Occupational
exposure to isopropyl alcohol. March 1976.
NIOSH. Registry of Toxic Effects of Chemical Substances.
1977.
Patty, F.A. (ed.). Industrial Hygiene and Toxicology, 2nd ed.
New York, Interscience Publishers, Inc. 1963.
Plaa, G.L. et al. Effect of alcohols on various forms of
chemically induced liver injury. Alcohol Liver Pathology
(Proceed-ings of the International Symposium on Alcohol and
Drug Research). 1975.
164
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Richardson, D.R. et al. Allergic Contact Dermatitis to "Alcohol1
Swabs. Cutis 5. 1115-1118, 1969.
Sanz, F. et al. (Standards for the study of teratogenic and
embryopathic action in dogs.) Arch. Inst. Farmacol Exp.
(Madr) 22(1-2), 7-11, 1970.
Sax, N. Irving (ed.). Dangerous Properties of Industrial
Materials, 3rd, ed. New York, Van Nostrand Reinhold Co.
1968.
Senz, E.H. and D.L. Goldfarb. Coma of a child following use
of isopropyl alcohol in sponging. J. Pediatr. 53, 322-323,
1958.
Van de Graaff, W.B. and W.L. Thompson. Isopropyl alcohol
intoxication. Arch. Intern. Med. 138(5), 826, 1978.
Vasiliades, J. et al. Pitfalls of the alcohol dehydrogenase
procedure for the emergency assay of alcohol: A case study of
isopropanol overdose. Clinical Chemistry 24(2), 383, 1978.
Verschueren, K. Handbook of Environmental Data on Organic
Chemicals. Litton Educational Publishing, Inc. 1977.
Wasilewski, C. Allergic Contact Dermatitis from Isopropyl
Alcohol. Arch. Dermatol. 98, 502-504, 1968.
Weil, C.S. et al. Quest for a suspected industrial carcinogen.
Arch. Ind. Hyg. Occup. Med. 5, 535-547, 1952.
Wills, J.H. et al. Effects on man of daily ingestion of small
doses of isopropyl alcohol. Toxicol. Appl. Pharmacol. 15,
560-565, 1969.
165
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CHEMICAL HAZARD INFORMATION PROFILE
Lithium and Lithium Compounds
Date of report: September 1, 1976
This group of compounds was chosen for study because of its
known effects on the nervous system and its suggested use as an
additive to drinking water.
Lithium and lithium compounds are not recommended for priority
evaluation within OTS at this time. None of the available informa-
tion indicates that these substances pose a hazard to human health
or the environment.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Lithium is the third lightest element and lightest of all
the metals, with an atomic number of 3 and an atomic weight of
6.939. The density of pure lithium is 0.531 g/ml. It melts at
180.5^C and boils at approximately 1,326°C. Lithium is present
as a trace element in many minerals, and makes up about 0.005% of
the earth's crust. Minerals richest in lithium are spodumene,
LiAlSi-Og,- petalite, LiAlSi.O,-; lepidolite, a complex mica; and
amblygonite, LiAlFP04. Litniam is the hardest alkali metal, but
is still very soft, rating 0.6 on the Mohs scale as compared with
10 for diamond and 1 for graphite. Lithium is present naturally
166
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as two isotopes: lithium-6, making up 7.39% of natural lithium,
and lithium-7, comprising the remaining 92.61%. Lithium-6 has
the ability to gain a neutron, which converts it to the heavier
isotope. Lithium has the highest heat capacity of any element in
both liquid and solid phases: 0.83 cal/g°C at 25°C and 1.37
cal/g°C at,190°C. It is a very reactive metal, combining spon-
taneously with nitrogen, hydrogen, and water, and when heated
will burn in the air. Unlike other alkali metals, the reaction
with water is not violent enough to ignite the hydrogen evolved.
Lithium can form covalent bonds to carbon, and reacts with most
organohalides to form organolithium compounds. Lithium ions will
form ionic salts with a wide range of anions. Some of the more
important compounds are outlined below.
Lithium acetate, commonly used as the dihydrate, CI^COOLi-
2H20, is a white crystalline powder that will dissolve in either
water or alcohol. The dihydrate melts at 58°C in its water of
hydration, while anhydrous lithium acetate melts at 291°C.
Lithium aluminum hydride, LiAlH^, is a white crystalline
powder. It is stable in dry air at room temperature, but will
decompose in moist air or at temperatures above 125°C. It is
soluble in ether and reacts violently with water or alcohol. It
is a common laboratory reducing agent, active on carbonyl groups
as in aldehydes, ketones, and acid chlorides, but will not reduce
olefinic double bonds.
Lithium amide, LiNH2/ forms cubic crystals that are insol-
uble in anhydrous ether, benzene, or toluene. It begins to
decompose at 320°C and melts at about 375°C.
Lithium borates form a number of different crystalline
powders that are slightly soluble in water and insoluble in
alcohol. Anhydrous lithium metaborate, LiBC>2, melts at 849°C,
while the tetraborate, LiB407, melts at 917° C.
Anhydrous lithium bromide, LiBr, is a white granular powder
melting at 547°C and boiling at 1,310°C. It is quite hygroscopic
and will dissolve in water, alcohol, glycol, and ether.
Lithium carbonate, Li2C03, is the salt with the highest
lithium content by weight. It is a white powder that is slightly
soluble in water and soluble in alcohol. It begins to decompose
at temperatures above 600°C.
Lithium chloride, LiCl, a crystalline powder, will dissolve
readily in water, alcohol, acetone, and pyridine. Anhydrous
lithium chloride is very hygroscopic. A sample left open to the
air will dissolve in the water it adsorbs. The melting point of
the anhydrous salt is 608°C, and the boiling point is 1,382°C.
167
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Lithium fluoride, LiF, melts at 848°C and boils at 1,681°C.
It forms either cubic crystals or a fluffy white powder. It is
insoluble in water, but will dissolve in acid solutions.
Lithium formate monohydrate, HCOOLi«H2O, forms water-soluble
white or colorless crystals. When heated, the substance loses
water at 100°C and decomposes at about 230°C.
Lithium hydride, LiH, forms cubic crystals that melt at
680°C~It is an excellent source of gaseous hydrogen. One pound
of lithium hydride will react vigorously with water to release 45
ft^ of hydrogen. It undergoes many of the reactions of elemental
lithium and will only reduce such easily reduced organics as acid
chlorides.
Lithium hydroxide, LiOH, is a white granular powder. Anhy-
drouslithium hydroxide melts at 471°C and will dissolve readily
in water and slightly in alcohol. It will adsorb water or carbon
dioxide from the air.
Lithium iodide, Lil, will form a number of hydrated salts.
The trihydrate melts at 75°C, the dihydrate at 79°C, and the
monohydrate at 130°C. Anhydrous lithium iodide, a white granular
powder, melts at 469°C and boils at 1/142°C. It is sparingly
soluble in water and alcohol and dissolves easily in acetone.
Lithium nitrate, LiNOj, melts at 251°C. Its colorless
granules will dissolve in either water or alcohol.
Lithium oxide is a white powder that remains solid at tem-
peratures up to 1,700°C. Like lithium hydroxide, it is a very
efficient CC>2 adsorbent and will also adsorb water from the
atmosphere.
Lithium metasilicate forms orthorhombic needles that melt at
1,201°C. It is insoluble in water.
Organolithium compounds are very useful in preparative
organic chemistry because of the polar-covalent nature of the
carbon-lithium bond. They are highly reactive with CC>2 and 02
but not N2, and burn spontaneously in air. The most important
commercial species is n-butyl lithium.
Production
The most extensively mined lithium ore is spodumene, although
rich enough deposits of any lithium mineral could be utilized.
There are a large number of processes in use for the extraction
of lithium, but they are all variations of essentially two pro-
cesses. In one, ground spodumene and limestone are mixed and
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fired to 1,100°C. The resultant clinker is ground and hot-
leached with water, yielding impure lithium hydroxide solution
which is concentrated, filtered, and recrystallized to purity.
In the other process, ground spodumene is heated at about 110°C
to convert it from the alpha to the more active beta form. This
is ground and mixed with hot sulfuric acid. Hydrogen replaces
lithium in the mineral, yielding soluble lithium sulfate. After
filtration to remove the insoluble residue, sodium carbonate is
added to the liquor to precipitate lithium carbonate, which is
then purified by washing and recrystallization. Lithium can also
be separated from brines, though this is not commercially feasible
in most cases unless produced as a by-product in the separation
of salts such as potash or borax. The by-product waste brines
are treated with hot sulfuric acid to separate the alkali sul-
fates. Sodium carbonate is added to precipitate lithium car-
bonate. Lithium carbonate is produced as the main product in
Silver Peak, Nev., where the brine has an unusually high Li
content of 300 ppm.
Lithium salts such as the acetate, bromide, chloride, flu-
oride, formate, iodide, nitrate, or sulfate can be made by mixing
lithium carbonate or hydroxide with aqueous solutions of the
appropriate acid. Ammonia gas will combine with hot lithium
metal to produce the amide. Lithium carbide and hydride can be
produced by direct combination of the heated component elements.
Lithium hydroxide solution and hydrogen peroxide yield lithium
peroxide, and the calcination of lithium carbonate with silica
yields lithium metasilicate. Organolithium compounds are pre-
pared by reacting finely divided metallic lithium in mineral oil
with the appropriate organohalide.
Pure lithium metal is commercially produced by electrolysis
using a 55 wt% LiCl/45 wt% KC1 electrolyte at temperatures of
about 460°C. Using a low-carbon steel cell and a graphite rod
anode, about 98% of the lithium can be recovered at a purity of
at least 99.8%. Lithium metal is marketed in 1/4-, 1/2-, 1-, and
2-lb ingots, ribbon, wire, rod, and shot, and as dispersions in
mineral oil.
No data on the production or consumption of lithium and
lithium compounds are available from the literature. Production
of lithium in 1968 has been estimated at 2,900 tons for the
United States and 4,700 tons for the world (Mineral Facts and
Problems, 1970). The growth rate is expected to parallel that of
the gross national product.
Major producers of lithium and lithium chemicals include
Foote Mineral Co., Lithium Corporation of America, and Harshaw
Chemical Co.
169
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Use
Lithium metal loses its extreme reactivity when combined
with other metals into alloys. When combined with aluminum,
lithium greatly increases the tensile strength of the material.
Lithium-magnesium alloys have the highest strength/weight ratio
of any structural metal. One alloy/ LA141, containing 85% mag-
nesium, 14% lithium, and 1% aluminum, has found 'extensive appli-
cations as a structural material in the aerospace industry.
Lithium was used as a fuel for the first series of hydrogen
atomic bombs. Because of the high reactivity of lithium with
oxygen and nitrogen, it has found use in metallurgy as a degasser
and scavenging agent in molten metal. Potential future uses for
lithium metal include utilization as the anode in high-energy
batteries, as in electric cars. The expansion of the atomic
power industry will also provide applications. Because of its
ability to absorb stray neutrons, lithium-6 would make an excel-
lent radiation shield for nuclear reactors. Its high heat
capacity would also make lithium an ideal heat exchange medium
for such thermonuclear reactors. The chief problem for this
application has been to find a container with which molten
lithium will not react.
Lithium acetate is used in organic synthesis, especially in
the preparation of medicinal formulations. It is a good catalyst
for the alcoholysis route of alkyd resin manufacturing.
Lithium aluminum hydride is a common laboratory reducing
agent, and also finds use in the preparation of other hydrides.
Lithium amide is used extensively in the pharmaceutical
industry for the synthesis of antihistamines. It is also used in
Claisen condensations, alkylations of nitriles and ketones, and
the synthesis of ethynyl compounds and acetylenic alcohols.
Lithium borates are used in the ceramics industry and in the
formulation of special-purpose glasses and enamels. Lithium
metaborate is also used as the matrix material for X-ray spec-
troscopy.
Lithium bromide is used in the laboratory as a catalyst and
dehydrohalogenating agent. It was used briefly in medicine as a
hypnotic and sedative. Anhydrous lithium bromide is used as a
dehumidifier in air conditioning systems, and 54-55% lithium
bromide brine is similarly utilized in adsorption refrigeration
systems.
Lithium carbonate is the starting material for the prepara-
tion of many other lithium salts. It finds use in the ceramics
industry for the formulation of various enamels, glasses, and
glazes. More recently, lithium carbonate has been used in the
170
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treatment of manic-depressive psychosis and other types of
psychological illnesses.
Lithium chloride is the raw material for the production of
lithium metal. It is also used in brazing fluxes, as an electro-
lyte for low-temperature dry cells, and as a dehumidifier in air
conditioning systems.
Lithium fluoride is used as a brazing and welding flux as
well as in the preparation of enamels, glasses, and glazes. It
also finds special applications in molten bath chemistry.
Lithium hydride is a very efficient source of gaseous hydro-
gen and as such has been used as a compact source of lighter-
than-air gas for balloons. Many of the applications of lithium
metal also apply to lithium hydride; it can be used as a heat
sink and a shield for thermal neutrons.
Lithium hydroxide, like lithium carbonate, can be converted
to other lithium salts. Its most important use is in the manu-
facture of lithium stearate or other lithium soaps. These soaps
are combined with lubricating oil at a ratio of 1 part soap to 9
parts oil to produce grease that retains its desired properties
in a temperature range of -52° to 138°C. Lithium hydroxide is
used as an atmosphere-regenerating agent because of its ability
to adsorb carbon dioxide. It is also used as an electrolyte in
alkaline storage batteries.
Lithium hypochlorite, with 35% available chlorine, is used
as a sanitary agent for swimming pools and as the active ingre-
dient in a few laundry bleaches.
Lithium nitrate is used as a flame colorant in fireworks and
flares and as an etchant in glass manufacture.
Lithium oxide, like lithium hydroxide, is a very efficient
adsorbent for carbon dioxide and can be similarly used as an air
purifier.
Lithium peroxide is a more efficient atmosphere regenerator
than either lithium hydroxide or oxide since it contains 35%
active oxygen which is released upon reaction with carbon dioxide.
Lithium sulfate is used in glass formulations to produce
glass for special applications requiring extra strength.
Organolithium compounds are very useful and versatile tools
in organic synthesis, especially in the anionic polymerization of
conjugated dienes. They are used commercially to produce the
synthetic rubber polyisoprene.
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Health Aspects
There is no information in the literature concerning any
biological effects of lithium metal. However, because of its
high reactivity with water, any contact with living tissue will
produce deep burns. Organolithium compounds are similarly highly
reactive and should be handled with extreme care.
The preponderance of studies on the biological effects of
lithium compounds are related to its therapeutic use in psychi-
atric medicine. This aspect of lithium is summarized in the
appendix.
The following are toxic and lethal doses of lithium chemi-
cals to various organisms listed by the Registry of Toxic Effects
of Chemical Substances:
Substance
Route
Organism
Dose(mg/kg)
Lithium
Lithium carbonate
Lithium chloride
Lithium fluoride
Intraperitoneal
Oral
Oral
Oral
Oral
Oral
Oral
Parenteral
Intraperitoneal
Subcutaneous
Oral
Subcutaneous
Subcutaneous
Pregnant rat
Human
Rat
Pregnant rat
Dog
Rat
Rabbit
Pregnant rat
Mouse
Mouse
Guinea pig
Guinea pig
Frog
TD =360
LD:=2,000
TD
LD
LD
LD
10
10
50
90
lowest published toxic dose.
lowest published lethal dose,
lethal dose, 50% kill.
lethal dose, 90% kill.
An interesting correlation has been found between the lithium
content of drinking water and the death rate due to atherosclerotic
heart disease, both in the United States (Blachly, 1970) and in
Britain (Polumbo et al., 1973). The lithium levels in water of
cities with the lowest fatality rates approach that of seawater.
Lithium diminishes five major atherosclerotic heart disease risk
factors: hypertension, diabetes mellitus, uric acid levels, hypo-
manic behavior, and serum lipid levels (Voors, 1969) , and has also
been shown to relieve ouabain-induced cardiac arrhythmias in dogs
(Polumbo et al., 1973). The protective effect of lithium seems
clear and may indicate that it is a vital element.
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There has been some concern about the use of lithium during
human pregnancy, because of scattered data concerning the terato-
genicity of lithium in lower species. Lithium disrupts normal
blastulation in sea urchins (Gustafson and Lenicque, 1952), and
at concentrations above 75 ppm produces significant decreases in
survival rates of bass embryos (unpublished data from University
of Kentucky, 1975). Lithium at 1:300 parts in growth medium of
frog eggs for 6 hr produces irreversible and lethal morphological
damage during gastrulation (Blando-Hoegler, 1974). In the cul-
ture medium of Drosophila (fruit flies), 0.022 M lithium was
lethal to all developing eggs (King, 1953). Rats, rabbits, and
rhesus monkeys receiving up to 4.05 mEq/day orally during organo-
genesis produced completely normal offspring (Gralla and Mcllhenny,
1972). However, pregnant mice exposed to lithium for the first
10 days of pregnancy at levels approximating those used thera-
peutically produced significantly smaller litters than controls
and several offspring with cleft palate. No other types of
abnormalities were found (Szabo, 1970). In another experiment,
pregnant goats were infused with lithium chloride to yield blood
levels of 4.90 mg/ml. Seventy-five percent of the offspring were
aborted and showed complete liver degeneration, while those
surviving showed hepatic degeneration and necrosis (Boulos et
al., 1973). A register of lithium babies has been set up, and
the results to date indicate that the total rate of abnormalities
is not significantly different from a normal population, but that
the rate of congenital heart disease and the ratio of cardio-
vascular defects to total defects appear high (Weinstein and
Goldfield, 1975).
Lithium, when added to culture medium of sugar beets at 1
mEq/1, produces growth stunting of shoots and fibrous roots. At
8 mEq/1, the leaves begin to grow yellow and curl up. The mech-
anism for the toxic effect is believed to be competitive inhibi-
tion of potassium and calcium absorption (El-Sheikh et al.,
1971). Lithium at 10-100 mM has been reported as toxic to tomato
plants (Kabanov and Myasoedov, 1974), but at lower concentrations
it aids photosynthesis and respiration in tobacco plants (Ezda-
kova, 1962).
Environmental Aspects
Lithium makes up 0.005% of the earth's crust. Where it is
present in the soil as a result of degradation of lithium-con-
taining minerals, lithium ions are leached from the soil by
rainfall and enter the ground water and thus, ultimately, the
water supply. There are amounts of lithium released into the
water systems as wastes from industrial processes producing or
utilizing lithium chemicals. There is no evidence that any
abnormally high levels of lithium in the environment have resulted.
Analysis of water supplies in Texas yielded values for the
lithium concentration of 0.001 to 0.078 mg/1. The most concen-
trated lithium brine known contains 300 mg/1. There is virtually
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no danger that toxic amounts of lithium could be ingested from
environmental sources. Any effects on human health from envi-
ronmental encounters appear to be beneficial, and lithium enrich-
ment of drinking water has been suggested. Lithium is not known
to undergo bioaccumulation in any organism.
APPENDIX
Psychiatric Uses of Lithium'
Ever since Cade reported in 1949 that lithium could relieve
a manic episode in manic-depressive-type psychotic patients, a
great deal of research has been going on concerning the psycho-
active and metabolic effects of lithium ions. It was hoped that
from this research would come a better understanding of the
nature of mania and depression, but thus far the metabolic
effects of lithium appear to be as numerous and varied as the
mental conditions that it affects. This research has the poten-
tial to explain a great deal about the nature of emotion if all
the connecting factors can be determined, but thus far the
evidence has supported no particular hypothesis.
The greatest part of the research on the biological proper-
ties of lithium is being directed toward manic-depressive psycho-
sis. Obtaining firm results as to the efficacy of lithium in
treating any mental disease is difficult due to the problems in
firm diagnosis and in running well-controlled double-blind
experiments. However, it appears that the effectiveness of
lithium in halting acute mania is somewhere between 75 and 100% 1
to 2 weeks after the initiation of treatment. The evidence
concerning lithium as treatment in acute depressive episodes is
less clear, but some positive effects seem likely, especially
when the episode is part of a true cyclic manic-depressive
disorder. Even more interesting is the evidence that lithium has
a prophylactic action in preventing recurrent episodes, both in
manic-depressive psychosis and in unipolar recurrent depression
(Tupin, 1970). In these effects lithium is unique among drugs,
especially so in that there is no psychological effect of seda-
tion or any other disruption of thought. However, cases have
been reported where lithium has had a negative effect on manic-
phase creative output during hypomania (Polatin, 1972).
Because of the status of lithium as somewhat of a "wonder
drug," it has been used in other types of mental disorders.
However, most of the evidence is in the form of individual case
reports, so no firm conclusions can be drawn. Lithium has been
reported to cure the affective or manic-type hyperactivity in
schizo-affective disorders. It also supposedly prevents premen-
strual tension, some types of childhood and adolescent personal-
ity disorders, and some cases of psychomotor epilepsy (Tupin,
1970). Cases of particularly dramatic recovery have been
174
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reported in explosively aggressive, often criminal, individuals
(Sheard, 1971). Two common characteristics of many of these
disorders are aggressiveness and an episodic-repetitive course.
In spite of the amount of research that has been done on
lithium and manic-depressive psychosis, very little is understood
about either of them. The major problem is that the effects
lithium produces on the body are so numerous that those related
to psychologic activity cannot be distinguished from the irrele-
vant side effects. As a result, a number of hypotheses have
arisen, all of which are both somewhat supported and refuted by
the evidence at hand. These hypotheses fall into three general
types. One says that mania and depression are caused by the same
dysfunction and that one is an extreme form of the other. Another
outlook views the two problems as causing one another and being
so closely related that curing one prevents the other from
recurring. A third approach claims that mania and depression and
the effects of lithium on them are separate and not related. The
major effects of lithium on the body and some of the ideas these
observations have evoked are presented here.
Lithium ions have been observed to slow down the circadian
rhythm of a species of flowering plant and a small mammal. The
similarity of the manic-depressive cycle and its relation to the
human circadian cycle are called to attention as one explanation
of the therapeutic action of lithium (Englemann, 1973).
One natural area for observation on the effects of any psy-
choactive drug is neurotransmitter metabolism. Lithium acts to
increase neuronal turnover and metabolic degradation of norepi-
nephrine, a neurotransmitter commonly believed to have an excre-
tion increase during mania and decrease in depression, which may
or may not be an indication of central nervous system (CNS)
activity. Lithium decreases the availability of norepinephrine
at the receptor site and tends to increase the rate of its
metabolic degradation. These actions would explain the effect of
lithium -on mania but not on depression (Andreasen, 1971). How-
ever, it has also been proposed that the central nervous system
is in a state of hyperexcitability in depression as well as
during mania (Mellerup and Rafaelson, 1974). When exogenous
quantities of norepinephrine are made available to the CNS, the
effect is sedation rather than excitement (Ketu, 1972). Thus,
administration of lithium to manic or depressed patients could be
curing different degrees of the same problem. The effects of
lithium on serotonin, a CNS neurotransmitter whose role in
psychological illness is not known, are contradictory. The rates
of both synthesis and degradation are increased, with increased
synthesis predominating (Schubert, 1973; Perez-Cruet, 1971).
Lithium is also believed to block synthesis of acetylcholine, a
peripheral neurotransmitter (Vizi et al., 1972).
175
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The mode of action by which lithium interferes with the
action of many hormones and metabolically active chemicals,
including serotonin and norepinephrine, is through inhibition of
the enzyme adenylate cyclase. This enzyme catalyzes the produc-
tion of cyclic adenosine monophosphate (CAMP), which appears to
be a directly active chemical that mediates the action of many
hormones (Singer and Rotenberg, 1973). The blocking of this
pathway is responsible for many of the observed effects of
lithium, and could be the explanation of its antipsychotic effect.
Another observed side effect of lithium use is polydipsia or
excessive thirst and a lack of urine concentrating ability.
Administration of vasopressin, or antidiuretic hormone (ADH),
which increases the water reabsorbed by the kidney, has no effect
on this condition. This can be explained by the inhibition by
lithium of adenylate cyclase, since the action of ADH on the
renal concentrating mechanism is mediated by CAMP (Singer and
Rotenberg, 1973).
Under the influence of lithium, levels of glucagon, a
hormone stimulating breakdown of glycogen in the liver, increase,
resulting in a decrease in liver glycogen and increased levels of
glucose in the blood. Hepatic synthesis of cholesterol and
triglycerides also drops (Singer and Rotenberg, 1973). Accom-
panying the rise in circulatory glucose is increased uptake of
glucose by brain, muscle, and adipose tissue and conversion to
glycogen (DeFeudis, 1973). This explains the weight gain often
observed in lithium-dosed patients.
Lithium has also been reported to cause dramatic rises in
white blood cell (WBC) counts. In manic patients treated.with
lithium, WBC counts rose from averages of 9,000 to 12,000, while
WBC counts in depressed subjects saw average increases from about
6,000 to 7,900. The increase was attributed to an increase in
production of granulocytes. No reason for the changes was
proposed (Murphy et al., 1971).
Lithium is generally administered orally as lithium car-
bonate. It is absorbed very efficiently by the gastrointestinal
tract, with peak serum concentration after a single dose of
lithium being achieved in about 30 min. Lithium crosses cell
boundaries at a relatively slow rate, achieving a distribution
corresponding to that of total body water 5-6 days after.
Lithium distribution may vary with the organ and from individual
to individual. It appears to be relatively slow to cross the
blood-brain barrier, although this too varies (Herrero, 1973).
Lithium is excreted almost entirely in the urine, although small
amounts may appear in the feces. Sixty to 70% of the filtered
load is reabsorbed in the proximal renal tubule, where it com-
petes with sodium in the renal transport mechanisms, leading to
higher lithium retention in low-sodium situations (Singer and
Rotenberg, 1973).
176
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In treatment of acute affective disorders, lithium is given
to raise serum levels to 2.0 mEq/1 or until symptoms remit.
Prophylactic lithium levels usually range between 0.6 and 1.5
mEq/1 in the serum. The major hazard of lithium use is the
slight difference between therapeutic and toxic levels. Side
effects occurring occasionally at low doses and with serum levels
below 2.0 mEq/1 include mild abdominal distress, vomiting, poly-
urea, thirst, general muscle weakness, continuous fine tremor of
the hands, general fatigue or lethargy, some dermatologic lesions,
and goiter. Toxic signs occurring as serum levels rise to 2.0-
3.0 mEq/1 affect primarily the central nervous system and include
lethargy, slurred speech, anorexia, vomiting, diarrhea, stupor,
coma, convulsions, and coarse tremor. Increasing stupor, coma,
and convulsions appear at levels above 3.0 mEq/1. Toxicity may
occur through overdose, decreased sodium or water intake, or
intercurrent illness (Tupin, 1970). Serum level monitoring is
the usual procedure to assure the proper lithium levels and to
prevent toxic effects, but many patients appear to be particu-
larly sensitive to lithium, and cases where toxic effects and
even permanent damage to the central nervous system have occurred
at serum lithium levels below 2.0 mEq/1 have been reported (Cohen
and Cohen, 1974).
In face of the observed prophylactic action of lithium, it
is interesting that a relationship has been reported between high
lithium levels in drinking water and lower rates of admission to
mental hospitals in Texas (Dawson et al., 1972). However, the
true statistical significance of this report has been called into
question (Pokorny et al., 1972) , and the amounts of lithium
actually consumed, estimated at 0.1 mg/day, are far below those
prescribed in psychiatric use, approximately 900 mg/day.
REFERENCES
Andreasen, N. J. T. Mechanism of lithium carbonate in manic-
depressive illness. Dis. Nerv. Syst. 32_(5) : 335-341, 1971.
Blachly, P. Lithium content of drinking water and ischemic heart
disease. N. Engl. J. Med. 281;682, 1970.
Blando-Hoegler, C. F. A study of the effects of lithium chloride
on embryonic and tissue specific isoenzyme patterns of Rana
pipiens pipiens. Diss. Abstr. B 3J5_(5) :2036, 1974.
Boulos, B. M., B. Carnow, N. Naik, J. P. Bederka, R. F. Kauffman,
and D. L. Azarnoff. Placental transfer of lithium and environ-
mental toxicants and their effects in the new born. Fed. Proc.
3,2(3:1) :745, 1973.
Cade, J. F. J. Lithium salts on the treatment of psychotic
excitement. Med. J. Aust. 3_6:349, 1949.
177
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Cohen, W. J., and N. H. Cohen. Lithium carbonate, haloperidol,
and irreversible brain damage. J. Am. Med. Assoc. 230(a);1283-
1287, 1974.
Dawson, E. B., T. D. Moore, and W. J. McGanity. Relationship of
lithium metabolism to mental hospital admission and homicide.
Dis. Nerv. Syst. J33_(8) : 546-556, 1972.
DeFeudis, F. V. Actions of lithium on cerebral carbohydrate
metabolism. Res. Commun. Chem. Pathol. Pharmacol. 5(3):789-796,
1973.
denHertog, A., and E. J. Ploeger. Mechanism of action of lithium
salts. Psychiatr. Neurol. Neurochir. 76^(6) : 529-535, 1973.
Dutta, S. K., and A. Bhattacharyya. Lithium and its uses.
Bangladesh Pharmacol. J. 3_(4):5-12, 1973.
El-Sheikh, A. M., A. Ulrich, and T. C. Broyer. Effect of lithium
on growth, salt absorption, and chemical composition of sugar
beet plants. Agron. J. £5_:755-758, 1971.
Englemann, W. Slowing down of circadian rhythms by lithium ions.
Z. Naturforsch. 28^(11-12) :733-736, 1973.
Ezdakova, L. A. Effect of lithium top-dressing on photosynthesis
and respiration in tobacco leaves. Nauchn. Dokl. Vyssh. Shk.
Biol. Nauki 21:137-142, 1962.
Gilman, H., and J. J. Eisch. Lithium. Sci. Am. 208 (1); 88-102,
1963.
Gralla, E. M., and H. M. Mcllhenny. Studies in pregnant rats,
rabbits, and monkeys with lithium carbonate. Toxicol. Appl.
Pharmacol. 2JL (3) :428-433, 1972.
Gustafson, T., and P. Lenicque. Mitochondria in the developing
sea urchin egg. Exp. Cell Res. 3_:251-274, 1952.
Herrero, F. A. Lithium carbonate toxicity. J. Am. Med. Assoc.
2.26 (a) : 1109-1110, 1973.
Kabanov, V. V., and N. A. Myasoedov. Toxicity of alkali metal
cations for tomato plants. Fiziol. Rast. 21^(2) :391-397, 1974.
Ketu, S. S. Norepinephrine in the central nervous system and its
correlations with behavior. Brain and Human Behavior Symposium,
1972. p. 115-129.
178
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King, R. C. Effects of alkali metals ions in development of
drosophila, with special reference to lithium-induced abnorma-
lities. Proc. Natl. Acad. Sci. U.S.A. 39^(5) : 403-407, 1953.
Kirk-Othmer Encyclopedia of Chemical Technology. New York, John
Wiley & Sons. 1967.
Leung, A. S. Lithium carbonate. Can. Psychiatr. Assoc. J.
15^(2) :189-199, 1970.
Mellerup, E. T., and 0. J. Rafaelson. Heterogeneity and bio-
medical findings in manic-melancholic disorders. Acta Psychiatr.
Scand. 5_0(1) : 104-111, 1974.
Merck Index, 8th ed. Rahway, N.J., Merck & Co., Inc. 1968.
Mineral Facts and Problems. U.S. Bureau of Mines. 1970.
Murphy, D. C., F. K. Goodwin, and W. E. Bunney. Leukocytosis
during lithium treatment. Am. J. Psychiatry 127(11);1559-1561,
1971.
OPD Chemical Buyers Directory, 63rd ed. New York, Schnell Pub-
lishing Co., Inc. 1975.
Perez-Cruet, J. Stimulation of serotonin synthesis by lithium.
J. Pharmacol. Exp. Ther. 178(2);325-330, 1971.
Pokorny, A. D., D. Sheehan, and J. Atkinson. Drinking water
lithium and mental hospital admissions. Dis. Nerv. Syst.
33J10) :649-659, 1972.
Polatin, P. Lithium carbonate prophylaxis in affective dis-
orders: Clinical vs. research applications. Dis. Nerv. Syst.
7):472-475, 1972.
Polumbo, R. A., A. Branzi, J. S. Schroeder, and D. C. Harrison.
The antiarrhythmatic effect of lithium chloride for experimental
ouabain induced arrhythmias. Proc. Soc. Exp. Biol. Med.
14^(4):1200-1204, 1973.
Registry of"Toxic Effects of Chemical Substances. U.S. Depart-
ment of Health, Education, and Welfare. 1975.
Schubert, J. Effect of chronic lithium treatment on monoamine
metabolism in rat brain. Psychopharmacologia 32(3):301-311,
1973.
Sheard, M. H. Effect of lithium on human aggression. Nature
2^(5289) :113-114, 1971.
179
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Shopsin, B. Effects of lithium on thyroid function. Dis. Nerv.
Syst. 3_1(4) :237-244, 1970.
Singer, I., and D. Rotenberg. Mechanisms of lithium action. N.
Engl. J. Med. 2j}£(5) : 254-260, 1973.
Szabo, K. T. Teratogenic effect of lithium carbonate in the
foetal mouse. Nature 225;73-75, 1970.
Trieff, N. M., S. M. Frey, M. S. Rao, H. Bunce, and B. Herman.
Analysis for lithium in Texas drinking waters. Tex. Rep. Biol.
Med. 3.1(1) :54-78, 1973.
Tupin, J. P. The use of lithium for manic-depressive psychoses.
Hosp. Commun. Psychiatry 2JL (3) :73-80, 1970.
Unpublished data from the University of Kentucky. Toxicity of
metals to bass embryos. 1975.
Vizi, E. S., P. Illes, A. Ronai, and J. Knoll. Effect of lithium
on acetylcholine release and synthesis. Neuropharmacology
11(4):521-530, 1972.
Voors, A. W. Does lithium depletion cause atherosclerotic heart-
disease? Lancet 2/. 1337-1339, 1969.
Weinstein, M. R., and M. Goldfield. Cardiovascular malformations
with lithium use during pregnancy. Am. J. Psychiatry 132(5):529-
531, 1975.
180
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CHEMICAL HAZARD INFORMATION PROFILE
Maleic Anhydride
Date of report: August 1, 1978
This chemical was chosen for study because of TSCA Section
8 (e) submissions describing worker complaints following possible
exposure to the chemical.
The following recommendations are made regarding further OTE
evaluation of the possible health or environmental hazards of
maleic anhydride:
(1) Check the results of the reported rat carcinogenicity
study to determine if tumors were found at sites remote
from the injection site — The presence of remote tumors
indicates a greater potential for carcinogenic action.
(2) Check the status of maleic anhydride in OAQPS — They have
conducted some investigations of the chemical.
(3) Transmit this report to NIOSH and OSHA — Most exposure to
maleic anhydride apparently occurs in the workplace.
(4) Update this Chemical Hazard Information Profile based
on the above.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on the report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Synonyms: Cis-butendioic anhydride, 2, 5-furandione,
toxilic anhydride
CAS No. : 108-31-6
The following diagram illustrates the chemical structure of
maleic anhydride:
HC = CH
I I
181
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Maleic anhydride, 0^203, is a white crystalline solid with
an acrid odor. It melts at 52.8°C and boils at 202JjC. Maleic
anhydride is soluble in water, acetone, hydrocarbons, ether,
chloroform, and petroleum ether (ITII, 1976). It is also soluble
in ethyl acetate and benzene (Patterson et al., 1976) and slightly
soluble in carbon tetrachloride (Lowenheim and Moran, 1975).
Maleic anhydride is combustible, with an ignition temperature of
476.67°C and flammable limits of 1.4-7.1% volume in air (ITII,
1976).
Production and Use
Ninety-one percent of the total maleic anhydride produced in
the United States is formed through oxidation of benzene, 6%
through oxidation of n-butane, and 3% as a by-product of phthalic
anhydride production. Benzene is oxidized in the vapor phase with
a vanadium catalyst. Reaction gases include a maleic anhydride-
maleic acid mixture, carbon dioxide, water, and some unreacted
benzene (Lowenheim and Moran, 1975). n-Butane is also oxidized in
the vapor phase. CEH suggests that a complex phosphorus vanadium
catalyst is used, but no specific information is available (CEH,
1976).
Total production of maleic anhydride has increased at a 7.6%
annual rate from 1969 to 1974. In 1974 production increased by
only 2.8%, and in 1975 it decreased by 27% to 211 million Ib.
This decrease was caused by feedstock restraints and impact of the
recession. Production rates from 1975-80 are expected to rise at
an annual rate of 10%. In 1980, 16% production (as opposed to 6%
in 1976) should be based on n-butanes (CEH, 1976).
CEH lists 10 U.S. production companies operating in 1976.
Two, Amoco Chemicals and Ashland Chemical, were expected
to begin operation late in the year. Production capacities of
these companies were projected to be expandable to 90 million Ib
per year. Production of U.S. Steel was predicted to expand to 87
million Ib per year (CEH, 1976).
The U.S. manufacturers of maleic anhydride are listed below
for the year of 1976. U.S. capacity adds up to 485 million Ib.
This comprises 31% of the total world capacity (CEH, 1976).
182
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Production capacity
Manufacturer (10^ Ib/year)
Amoco Chemicals Corp., Joliet, 111. 60
Ashland Chemicals Co., Neal, W. Va. 60
Koppers Co., Bridgeville, Pa., 34
Chicago, 111. 10
Monsanto Industrial Chemicals Co., St. Louis, Mo. 105
Petro-Tek Chemicals Corp., Houston, Tex. 50
Reichhold Chemicals Corp., Elizabeth, N.J., 30
Morris, 111. 60
Tenneco Chemicals Inc., Fords, N.J. 26
U.S. Steel Corp., Neville Island, Pa. 50
All uses of maleic anhydride involve its application as a
chemical intermediate. In 1975, 58% of the total maleic anhydride
consumed in the Uu S. was used in unsaturated polyester
resins. Of these resins, 78% were used in reinforced plastic
applications and 22% in nonreinforced plastics and resins. Four
percent of the maleic anhydride consumed was used in the production
of fumaric acid, 9% in agricultural chemicals (malathion, maleic
hydrazide, and captan), and 3% in alkyd resins. Twenty-six %
of maleic anhydride was used in miscellaneous applications such as
lubricating additives, chlorendic anhydride and acids, copolymers,
reactive plasticizers, malic acid, and surface-active agents (CEH,
1976; SRI, 1977).
Health Aspects
Application of maleic anhydride consists only of use as a
chemical intermediate, limiting exposure to occupational sources.
The vapors and dust of maleic anhydride are acute irritants of
eyes, skin, and .upper respiratory tract. Maleic anhydride can
be a sensitizer of the skin and respiratory tract (ACGIH, 1971).
Subacute inhalation of maleic anhydride can cause severe
headaches, nosebleeds, nausea, and temporary impairment of vision.
It can also lead to conjunctivitis and corneal erosion (Kirk-
Othmer, 1968).
Patterson et al. (1976) state that repeated exposure to
concentrations above 1.25 ppm has caused asthmatic responses in
workers. Allergies have developed so that lower concentrations of
maleic anhydride cannot be tolerated. An increased inci-
dence of bronchitis and dermatitis has also been noted in
workers with long-term exposure to maleic anhydride. One case of
pulmonary edema in a worker was reported (Patterson et al., 1976).
183
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In rats, maleic anhydride has an oral TDL of 850 mg/kg.
Subcutaneous TDL is 610 mg/kg/61 weeks. Maleic anhydride is a
carcinogen in rats administered subcutaneously. Other toxic
effects are liver injury and histological changes (ITII, 1976).
Thome-beau et al. (1969) found that maleic anhydride strongly
inhibits the enzyme ATP thiamine pyrophosphotransferase. This
enzyme is a kinase which functions to catalyze the transfer of
phosphate from ATP or, much more infrequently, from another nucleo-
side triphosphate to its substrate.
Obaid et al. (1972) treated human red cells with maleic anhy-
dride. As a result of this treatment, potassium and sodium perme-
ability increased, sodium to a lesser extent. Permeability of
sulfate and chloride decreased to the same extent.
OSHA has set forth an 8-hr time weighted average of 0.25 ppm
in the air. The TLV is likewise 0.25 ppm. It is stated, however,
that further experience is needed to confirm or deny the suitability
of this limit (ACGIH, 1971).
Health Aspects of a Reaction Product, Benzene
Ninety-one percent of maleic anhydride produced in the U.S.
is formed through oxidation of benzene. Reaction gases
consist of benzene and maleic anhydride, among others (Lowenheim
and Moran, 1975).
Benzene has various toxic effects. Chronic effects include
anorexia, nausea, fatigue, weakness, dizziness, nervousness, and
irritability. Acute symptoms include stimulation of the central
nervous system, then depression, with death via respiratory paral-
ysis. Also involved are respiratory irritation, pulmonary edema,
and gastrointestinal irritation with vomiting and colic. Benzene
is also a carcinogen (ITII, 1976).
The separate effects of maleic anhydride and benzene are
fairly well documented. Data on the health aspects of exposure to
a combination of the two as reaction products are nonexistent.
Environmental Aspects
The largest quantity of maleic anhydride emitted (2.96 million
Ib per year) escapes as a result of phthalic anhydride production.
Other sources of emission are maleic anhydride production (0.85
million Ib), end product manufacture (0.85 million Ib), and product
handling and packaging losses (0.06 million Ib). The tptal amount
of maleic anhydride released from these sources is 4.72 million Ib
(Patterson et al., 1976).
184
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Patterson et al. have made estimates of maximum average con-
centrations for 1 and 24 hr. The maximum 1-hr concentration is
0.20 ppm, and the maximum 24-hr concentration is 0.10 ppm (Patter-
son et al., 1976) .
The primary method of emission control is to scrub the
uncondensed portion of the reaction effluent after it passes through
a partial condenser. Agaev et al. (1976) have found that maleic
anhydride can be detoxified by oxidation with a 97-98% efficiency.
Matsui et al. (1975) report that maleic anhydride in wastewater is
easily decomposed by test-activated sludge. Developmental
work is being done to control maleic anhydride emissions.
REFERENCES
ACGIH (American Conference of Governmental Industrial
Hygienists). Documentation of Threshold Limit
Values for Substances in Workroom Air, 3rd ed.
1971. p. 263.
Agaev, A. S. et al. Detoxification of phthalic anhydride
industry discharges. Khim. Tekhnol. Topi. Masel
11:44-45, 1976. (English abstract)
Chemical Economics Handbook (CEH). Maleic Anhydride.
Menlo Park, Calif., Stanford Research Institute.
July 1976.
ITII (International Technical Information Institute).
Toxic and Hazardous Industrial Chemicals Safety
Manual. Tokyo. 1976.
Kirk-Othmer Encyclopedia of Chemical Technology, 2nd
ed., vol. 12. New York, John Wiley & Sons. 1978.
Lowenheim, Frederick A., and Marguerite K. Moran.
Industrial Chemicals, 4th ed. New York, John Wiley
& Sons. 1975. p. 514-518.
Matsui, S. et al. Activated sludge degradability of or-
ganic substances in the waste water of the Kashima
petroleum and petro chemical industrial complex in
Japan. Prog. Water Technol. 7^:645-659, 1975.
NIOSH. Registry of Toxic Effects of Chemical Substances.
1975.
Obaid, A. L. et al. Effects of maleic anhydride on the
ionic permeability of red cells. J. Membr. Biol.
9^:385-401, 1972.
185
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Patterson, R. M. et al. Assessment of maleic anhydride as a
potential air pollution problem. U.S. NTIS, PB Report,
Issue PB-258363, 1976.
SRI (Stanford Research Institute). A Study of Industrial
Data on Candidate Chemicals for Testing. Menlo Park,
Calif. August 1977.
Thome-beau, F. et al. ATP thiamine pyrophosphotransferase.
Purification and reaction. Biochim. Biophys. Acta
185:11-21, 1969.
186
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CHEMICAL HAZARD INFORMATION PROFILE
Methanol
Date of report: July 11, 1977
This chemical was chosen for study because of projected trends
in production and use patterns.
It is recommended that a more comprehensive literature search
be performed on methanol. The CHIP report will then be revised
and the review process repeated.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Methanol or methyl alcohol, CH3OH, is a colorless neutral
liquid at ambient temperature with a mild odor. It has a boiling
point of 65°C and is infinitely soluble in water, alcohol, and
ether. By far the largest use of methanol is in the production
of formaldehyde (CEH, 1976).
Production and Use
At present, the most important method of methanol manufacture
is by a high-pressure process involving a pressurized synthesis gas
(usually made by the re-forming of straight natural gas and consist-
ing of a mixture of CO, CO-, and H2) which is converted into
methanol according to the following reactions:
CO + 2H2 CH3OH
C02 + 3H2 CH3OH + H20
Essentially all methanol manufactured in the U. S. is
based on natural gas. In a typical high-pressure process, the
synthesis gas is desulfurized, cooled to remove steam, compressed
to 4,300 psi, mixed with recycled gas, and passed to the converter.
The conversion to methanol takes place at temperatures around 300°C
in the presence of a zinc-chromium catalyst. The methanol-containing
gases are then cooled, condensed, and purified by distillation.
Methanol of 99+% purity and an overall yield of 60% from natural
187
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gas may be obtained by these high-pressure processes. The low-
pressure processes are responsible for the balance of domestic
synthetic methanol production (roughly 30-40%). This method
operates at pressures around 750 psi and at temperatures near
250°C. There are various other differences between high- and
low-pressure processes, with the end result being a purer crude
methanol, greater production efficiency, and lower operating costs
for the low-pressure process. See Tables 1 and 2 for domestic
production figures and a listing of producers. Several companies
have developed medium-pressure processes; however, no domestic
plants are currently using this method. Various other processes
contribute small amounts of methanol to overall domestic produc-
tion, although none are presently of great significance.
The largest end use for methanol is in the production of
formaldehyde. Other large-volume chemicals based on methanol
include dimethyl terephthalate, methyl halides, methylamines,
methyl methacrylate, and various solvent uses, among others. See
Table 3 for a more complete breakdown of the methanol consumption
figures.
Methanol was in tight supply at points in 1973-74. However,
the recession has cut demand, and the supply has been adequate from
1975 to the present. Methanol may become scarce again when the
building industry picks up and demand for formaldehyde resins
increases. New plants, slated to come on stream in 1979 and
19B"0, will relieve the shortfall..
The price of methanol has increased significantly since 1973
and is expected to continue upward (CEH, 1974).
New Developments
Methanol from Coal. The growing scarcity of natural gas in the
United States has resulted in an increased interest in producing
methanol from coal. Several companies have studies coal
gasification units which utilize a variety of methods. A number of
these proposed methods are currently being tested in pilot plants.
In most processes, coal is fed to a gasifier, where the raw material
reacts with steam to produce hydrogen gas and carbon monoxide. The
raw gas is then processed to remove sulfur. The clean synthesis
gas is subsequently used to produce methanol.
Table 1. Annual Domestic Methanol Production (10^ ib)
Year Natural Synthetic Total
1960
1965
1970
1975
14.3
8.8
10a
10a
1,965.9
2,868.6
4,931.7
5,176.3
1,980.2
2,877.4
4,931.7
5,176.3
asource: CEH, 1976. Approximation.
188
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Table 2. Domestic Producers of Methanol and 1974 Capacity
Capacity
Producer/location (106 Ib)
Air Products and Chemicals, Inc. 332
Pensacola, Fla.
Borden Chemical
Geismar, La. 1,061
Celanese Corp.
Bishop, Tex. 398
Clear Lake, Tex. 1,525
Commercial Solvents Corp.
Sterlington, La. 332
E. I. du Pont de Nemours & Co.
Beaumont, Tex. 1,326
Orange, Tex. 762
Georgia-Pacific Corp.
Plaquemine, La. 663
Hercules, Inc.
Plaquemine, La. 663
Monsanto Co.
Texas City, Tex. 663
Rohm and Haas Co.
Deer Park, Tex. 146
Tenneco Inc.
Houston, Tex. 530
Source:CEH, 1974.
189
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Table 3. Domestic Consumption of Methanol (%)
1968 1973
Formaldehye
Solvent usagea
Dimethyl terephthalate
Methyl halides
Methylamines
Methyl methacrylate
Acetic acid
Glycol methyl ethers*3
Inhibitor for formaldehyde0
Exports^
Miscellaneous6
44.7
9.9
5.5
5.4
4.2
4.1
0.2
1.9
1.2
1.9
20.9
39.0
7.9
6.1
6.1
3.3
3.7
3.4
1.1
0.9
11.6
16.9
Source: CEH, 1974.
aMethanol is used as a solvent for many substances
including: dyes; nitrocellulose and ethyl cellulose;
polyvinyl acetate; butyral shellac and modified resin;
others.
^The single largest use for ethylene glycol monomethyl
ether is as a deicing agent in jet fuels; it also finds
use as a solvent for protective coatings (mainly lacquer
formulations) and in textile dyeing processes. Ethylene
glycol monomethyl ether is also used as an intermediate
for di(2-methoxyethyl)phthalate plasticizer production.
cFormaldehyde has a tendency to polymerize on storage, so
methanol is sometimes added (about 0.03 Ib of methanol
per Ib of 37% formaldehyde) to inhibit polymerization.
^1966-68 were light years for the export of methanol;
no explanation was offered.
eMethanol is used in the production of numerous other
chemicals (e.g., methyl acetate, dimethylaniline, methyl
acrylate, o-nitroanisole, sodium methylate, polyphenylene
oxide, and dimethyl phthalate), though none represents
a significant end use for methanol by itself. Very
little methanol is currently used as an antifreeze in
automobile engines because of the high operating tem-
peratures of modern engines. An estimated 50 million
Ib of methanol was used in 1970 as a deicer in gasoline,
and this market is expected to grow moderately. Seventy-
five million Ib of methanol was used in 1969 as an
antidetonant injection fluid in aircraft fuel? this use
of methanol, however, is being phased out for unknown
reasons.
190
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To date, no plants have been built in the United States
for this purpose. However, a West German commercial gasification
operation is slated to come on stream in 1978. An unnamed
industry source believes that the first large, domestic
coal-based methanol unit will not come much before 1982.
However, if this initial plant proves successful, others are
likely to follow.
The major difficulties to be overcome are those associ-
ated with gas cleanup and the various engineering design
problems involved with the incorporation of a methanol
synthesis unit in a gasification plant. A coal conversion
plant would most likely be based on lignite or bituminous
coal (CEH, 1976).
Sewage Treatment Applications. A potentially large use for
methanol is as a carbon source for bacteria to aid in the
(anaerobic) conversion of nitrates to nitrogen gas and
carbon dioxide gas. Methanol is regarded as the most appropriate
source of carbon for denitrification in an activated sludge
or trickling filter installation because of .its low cost and
miscibility with water. Washington, D.C., was scheduled to
begin using methanol for this purpose in 1975; if the project
succeeds, other communities are expected to follow the
Washington lead. Estimates for this market are 30 million
gallons in 1979 and 392 million gallons by 1985 (CEH, 1976).
Production of Animal Feed. Another use for methanol may be
as a substrate for the fermentation production of animal
feed protein (single-cell protein). A domestic pilot plant
is in operation at Bartlesville, Okla.; however, the use of
single-cell protein is on a small scale in the United States
because of low soybean prices, a restricted market, and
resistance to its use by humans. This market is not expected
to be.come significant in the United States during the next 5
years (CEH, 1976).
Mega-Methanol Plants and Liquid Chemical Fuel. During the
past several years,considerable worldwide interest has been
stimulated in the manufacture of massive quantities of
methanol for use as a direct fuel or as a feed for conversion
to substitute natural gas (SNG). The original intention was
to divert currently flared Middle East natural gas to liquid
chemical fuel (an impure form of methanol) production. The
methanol thus produced would be shipped to the United States
for use directly as a fuel or for regasification to SNG.
Several projects were started in 1973 but were subsequently
cut back or phased out.
191
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The impetus for construction of mega-methanol plants
comes from the potential cost savings obtained from the
long-distance shipping of liquid chemical fuel (LCF) as
opposed to liquefied natural gas (LNG). Despite higher
production costs for LCF, methanol is far cheaper to ship
because it can be carried in conventional crude oil tankers.
LNG, on the other hand, must be shipped in expensive cryogenic
tankers. Following delivery, LCF is also cheaper to store.
Nevertheless, very large methanol-producing plants would be
needed to make LCF production economically feasible. Without
a large capacity, it is doubtful that a plant could keep a
fleet of tankers operating steadily and economically. The
break-even mileage beyond which LCF is more economical to
ship than LNG is debatable. Industry estimates range from a
low of 1,800 miles to as high as 5,000-6,000 miles.
Methanol fuel plants were formerly seen for locations
with abundant cheap natural gas. The Arab oil embargo,
however, has shifted interest to domestic coal-based facilities.
Construction of mega-methanol plants has been held up for
two reasons: coal-based technology has not been tested out
on a commercial scale, and a tremendous amount of capital is
required to build such a plant. One estimate places the
investment at $1 billion for the first 10,000-tons-per-day
methanol plant. The uncertainty of performance and the
possibility of failure combine to restrain investors.
Nevertheless, forecasted demand for all nonchemical uses of
methanol indicates that the demand by 1990 could equal the
production from several mega-methanol plants (CEH, 1976).
Use as a Motor Fuel. In 1968, an estimated 66 million Ib
(10 million gal) of" methanol was used as a fuel (in modified,
predominantly racing engines) and as a fuel additive (e.g.,
for increased thrust in turbine engines). These end uses
were expected to increase to 100 million Ib (15 million gal)
by 1973. Although methanol use as a fuel in special situations
was expected to continue upward, it was not seen as a large
market because methanol tends to clean out rust in storage
tanks and piping resulting in contaminated fuel. During the
gasoline shortage of a few years back, however, interest in
using methanol as an automobile fuel or fuel extender was
renewed. The situation at that time made the issue of fuel
availability more important than the greater production
costs of methanol.
Although methanol can be used directly as an automobile
fuel, it is more likely in the near term to find use in fuel
blends. Use of methanol as a fuel extender obviates the
need for engine and other modifications necessary in a
conversion of cars from gasoline to liquid chemical fuel
(design changes are possible in new cars, but to retrofit
old cars is costly). Several test cars have been successfully
operated on methanol or methanol/gasoline mixtures. The
advantages of blends are reduced emissions and improved
octane rating; the disadvantage is engine stalling resulting
from phase separation following moisture pickup. Although
192
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this can be solved technically, it would result in higher
fuel distribution and handling costs. Other problems (vapor
lock, hard cold-weather starting, corrosion problems, incom-
patibility with plastics, etc.) can also be solved with the
proper modifications, or so the proponents of fuel blends
claim.
Some quarters (e.g., the American Petroleum Institute)
feel that straight methanol is preferable to the use of
blends with gasoline for automobiles. Liquid chemical fuel
and high methanol blends are cleaner burning, have greater
fuel efficiency (usable at higher compression ratio than
gasoline), and are not susceptible to phase separation.
Nevertheless, because of supply problems and the inability
of cars built for methanol to run on gasoline, straight
methanol is foreseen only for use in taxis, municipal cars,
or fleet operations in the near term.
During the next 5 years, consumption of methanol for
automobile fuel applications is expected to remain small.
One estimate places worldwide use of methanol for this
purpose at 11 to 176 billion Ib by 1985; another estimate is
less optimistic and predicts that worldwide automotive fuel
demand in 1985 will be 23 billion Ib.
Methanol can also be used to produce methyl tertiary
butyl ether (MTBE), an octane improver. Although there is
competition from other materials, it has been estimated that
at least 2.9 billion Ib of methanol could be used for world-
wide MTBE production in 1985 (CEH, 1976).
Gasoline from Methanol. Industry is developing a process
for producing octane gasoline from methanol by examining the
possibility of coupling the new technology with existing
methanol processes to provide a new gasoline source from
coal. The two-stage process has an anticipated yield of 90%
(75-80% high-quality gasoline and the balance in less desirable,
though usable, hydrocarbons). Another process attempts to
convert coal to ethylene and produce substantial quantities
of gasoline as a by-product. A demonstration plant using
this process is under construction and, if it proves success-
ful, offers the possibility of making either ethylene or
gasoline as demand warrants. During the next 5 years,
methanol demand for ethylene-gasoline production is expected
to remain small. Nevertheless, some in industry feel that,
in the long term, this process will offer tremendous opportun-
ities for gasoline production (CEH, 1976).
Power Generation. One of the potentially largest new markets
for methanol is power generation in peak loading gas turbines.
Projected domestic methanol demand for this purpose is
forecast at 29 billion Ib by 1985. The basis for the
optimistic projection is the foreseen increasing demand for
gasified coal as a fuel. A coal gasification plant is very
capital intensive; to ensure maximal utilization, the proposal
is to use synthesis gas as fuel for power generation at
times of peak demand and divert some of the gas to methanol
193
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production during off-peak hours. The stored methanol could
be used to cover fuel shortages during peak electricity
demand periods. Presently, there is not enough methanol
available to operate a gas turbine in this manner, and until
the mega-methanol plants (likely coal based) are built, this
methanol market will not develop (CEH, 1976).
In Coal Slurry Pipelines. An Alaskan proposal suggests the
use of methanol in lieu of water as the basis for a coal
slurry which would be transported to southern California by
tanker. The proposal is of interest in the western regions
of the country also. There are a number of pluses to this
idea: it would help alleviate concerns about the large
volume of water diverted from agriculture to such large-
scale industrial ventures; it is claimed that methanol can
carry 75-80% coal, compared to 50% for water; and the
pipeline could run economically at only 25-30% capacity.
This concept also awaits the development of mega-methanol
plants and is not expected to be significant before 1981
(CEH, 1976).
Miscellaneous. Methanol could conceivably be used in substantial
quantities by the steel industry, either as a source of
synthesis gas or of pure hydrogen. The ease of transport of
methanol is the big plus in this potential market. Industry
estimates vary from no substantial use of methanol in blast
furnaces by 1985 to 75 to 95 million metric tons of methanol
consumed worldwide by the same date for this purpose.
Another possible market is as a feedstock for reducing
gas generation. Methanol could be used as a precursor of
hydrogen or synthesis gas, especially for the direct reduction
of iron ore. Estimated methanol consumption in this area
could account for 9 to 12.5 million metric tons per year
worldwide by 1985.
Methanol has also been suggested as an alternate starting
material for the synthesis of ammonia (CEH, 1976).
Health Aspects
Human
The toxic effects of methanol exposure are generally
the same following both acute and chronic exposure. The
underlying basis for this is the slow metabolic breakdown
and removal of methanol and its by-products from the body
such that a chronic response appears to be the result of a
cumulative increase in these substances. Most instances of
acute lethality follow the oral ingestion of methanol.
Nevertheless, the symptomatologies of oral and inhalation
exposure appear to be identical, though often less severe
for the respiratory route.
194
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Methyl alcohol is readily absorbed from both the gastroin-
testinal and respiratory tracts. The lethal dose in man
lies between 2 and 8 oz, implying a high variation in individual
susceptibility.
Mild and transient inebriation followed by drowsiness
are immediate effects of methanol ingestion. This phase is
followed by a symptom-free period of 6 to 30 hr, after which
characteristic signs and symptoms of methanol poisoning
develop: nausea, epigastric pain, vomiting, headache,
narcosis, dizziness, delirium, blindness, acidosis, and
acetonuria, among others (Treon, 1963; Gleason et al.,
1969) .
Acidosis appears to be the triggering mechanism for
most symptoms of methanol poisoning regardless of route.
Acidosis results from the metabolic oxidation of methanol to
formic acid and also because of the unexplained tendency of
other organic acids (e.g., lactic acid) to accumulate in the
body. The severity of the response to methanol is said to
be related to the intensity of this delayed acidosis.
Visual disturbances are the most distinctive aspect of
methanol poisoning in man (Gleason et al., 1969). The
effect on the eyes is attributed to optic neuritis, which
characteristically subsides only to be followed by degeneration
of the optic nerve, often leading to permanent blindness
(Sax, 1968). It is generally agreed that metabolically
formed formaldehyde is responsible for the ocular difficulties
(Gleason et al., 1969).
A concentration of 2,000 ppm is barely detectable by
odor and not irritating to man. Instances of fatal respiratory
expo-sure are rare, but include a woman exposed to a calculated
4,000 to 13,000 ppm for 12 hr and a man exposed to 40,000
ppm for part of a working day. On the basis of human exposure,
it was calculated that repeated 8-hr exposures to 3,000 ppm
of methanol will lead to increasing concentrations of the
alcohol and its toxic metabolites within the body due to the
slow rate of excretion.
Skin absorption of the liquid and vapor can occur, but
is not likely to lead to toxic effects. An estimated 1 oz
of methanol must be absorbed through the skin to affect man
(Patterson et al., 1975).
Human pathology studies of methanol fatalities (oral)
have revealed damage to the gastrointestinal tract, lungs,
liver, pancreas, spleen, and neurons of the brain (Treon,
1963).
Laboratory Animals
Death in animals (nonprimates) following exposure to
methanol is not due to acidosis, but to narcotic effects
exerted on the central nervous system. Lab animals apparently
have a greater alkaline reserve with which to combat acidosis
195
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than does man. Nevertheless, the susceptibility of animals to
methanol varies with species and even among individuals of the
same species.
Exposure to acute concentrations will generally produce the
following responses in animals: increased breathing rate, nervous
depression followed by excitation, irritation of mucous membranes,
ataxia, partial paralysis, narcosis, convulsions, weight loss, and
death due to respiratory failure. Necropsies have revealed consid-
erable central nervous system degeneration (Treon, 1963).
Hygienic Standards
Methanol's international hygienic standards are as follows:
United States, West Germany, and Sweden, 260 mg/m (8-hr TWA); East
Germany and Czechoslovakia, 100 mg/m^ (8-hr TWA); U.S.S.R., 5 mg/m^
(acceptable ceiling concentration) (Winell, 1975).
Environmental Aspects
Losses
Emissions of methanol from solvent usage represent the largest
category of losses to the environment. These sources, however,
tend to be small and geographically scattered. Production emis-
sions represent only a small portion of total methanol release.
Nevertheless, because the losses tend to be heavily localized and
not disperse as in the case for solvents, this source could repre-
sent a problem.
MITRE Corp. (1976) and Patterson et al. (1975) estimate the
annual environmental loss of methanol at approximately 18% of total
production. Thus, the Patterson et al. figure for 1974 is 1,242
million Ib, while the MITRE value for 1975 (which suffered a 1.6
billion Ib production decline) is 988 million Ib. As noted pre-
viously, the largest loss category is solvents, which represent
approximately 90% of all methanol losses. Production, handling,
and end product manufacture represent the remaining 10%. See Table
4 for a listing of sources and their estimated emissions.
Table 4. Methanol Source and Emission Estimates
(based on production of 6.7 billion Ib)
Emissions3
Source (106 Ib/year)
Miscellaneous solvent usage 575
Industrial solvent usage 538
Methanol production 68
End product manufacture 49
Storage and handling 12
Total 1,242
asource:Adapted from Patterson et al.,1975
Based on 100% loss of solvents and 1% loss during
production of methanol and end products.
196
-------
The proposed mega-methanol plants may represent an appreciable
hazard, especially if they tend to be clustered. If the 1% loss
figure is accurate, the emissions from a single 10,000-metric-ton-
per-day mega-methanol facility would be over 800 million Ib per
year. Couple with this the losses expected from the other proposed
uses, especially as an auto fuel, and the increase in total emis-
sions arising solely from the expected growth in present-day uses
of methanol, and one can appreciate methanol's potential for caus-
ing future health and environmental problems.
Atmospheric Chemistry
Methanol is not a significant component of photochemical smog,
nor is it very active in the formation of photochemical products
following irradiation (Patterson et al., 1975). Methanol, however,
is reactive with oxidizing material in the atmosphere (MITRE Corp.,
1976). Because of methanol's water solubility, rain would be
expected to remove some from the air.
Effects on Vegetation
Methanol has not been implicated in vegetation damage as have
various other pollutants. However, a recent Russian study (refer-
ence unknown) has indicated that plants may be sensitive to metha-
nol vapor. Concentrations above 0.2 mg/m3 (0.15 ppm) produced a
decrease in photosynthesis in several different tree species. This
finding may be significant because it seems to indicate that plants
are more sensitive to lower concentrations of methanol vapor than
are either man or animals (Patterson et al., 1975).
Effects on Inanimate Objects
Methanol as a solvent will attack some types of plastics,
coatings, and rubbers (Patterson et al., 1975).
REFERENCES
Chemical Economics Handbook (CEH). Menlo Park, Calif., Stanford
Research Institute. 1974, 1976.
Gleason, Marion et al. Clinical Toxicology of Commercial Products,
3rd ed. Baltimore, The Williams and Wilkins Co. 1969.
MITRE Corp. Scoring of Organic Air Pollutants. Chemistry,
Production and Toxicity of Selected Organic Chemicals. (For
U.S. Environmental Protection Agency) 1976."''
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some informa-
tion is not possible. The environmental release data were taken
from the NSF/Rann Research Program on Hazard Priority Ranking of
Manufactured Chemicals.
197
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Patterson, Robert M. et al. Assessment of Methyl Alcohol as a
Potential Air Pollution Problem, vol. II. U.S. Environmental
Protection Agency. 1975.
Sax, N. Irving (ed.). Dangerous Properties of Industrial Materials.
New York, Van Nostrand Reinhold Co. 1968.
Treon, Joseph F. In Frank A. Patty (ed.), Industrial Hygiene and
Toxicology, vol. II. New York, Interscience Publishers.
1963. p. 1409-1422.
Winell, Margareta. An international comparison of hygienic standards
for chemicals in the work environment. Ambio 4:34-6, 1975.
198
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CHEMICAL HAZARD INFORMATION PROFILE
Methylamines
Date of report: May 1, 1978
These chemicals were chosen for study because of their poten-
tial for being nitrosated and thereby forming nitrosamines. Cer-
tain nitrosamines are known carcinogens.
The following recommendations are made regarding further OTE
evaluation of the possible health or environmental hazards of
methylamines:
(1) Refer to OSHA—Most exposure to methylamines is confined
to the workplace. There is a reported incident of fisher-
men fainting due to excessive concentrations of trimethyl-
amine.
(2) Check on DOT status—Determine the potential for accidental
spillage.
(3) Refer to OAQPS—Amines may be released into the air from
manufacturing sites.
(4) Require Section 8 (a) submissions--Determine the presence
of methylamines in consumer products and revise this
Chemical Hazard Information Profile accordingly.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
All the methylamines are gaseous under normal temperatures and
pressures. They have an ammonia-like odor, are quite basic, and
are soluble in water and lower alcohols. Their salts are often
used because they are solids of low volatility and thus more easily
handled (Harwood, 1971). Respective pKa and boiling point (°C)
values for the methylamines are monomethylamine, 10.64, -65;
dimethylamine, 10.61, 7.4; and trimethylamine, 10.71 and 3.5
(Button, 1963).
199
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Production and Use
The methylamines are produced by reacting ammonia and methanol
over a dehydrating catalyst. In 1973 the total domestic methyla-
mine production capacity was 243 million Ib. In 1975, 37 million
Ib of dimethylamine and 14 million Ib of trimethylamine were sold.
A significant portion of the methylamines produced are used cap-
tively as intermediates and are not sold (U.S. ITC, 1975). Produc-
tion data from 1977 are as follows: Monomethylamine 60 million Ib;
Dimethylamine 100 million Ib; and Trimethylamine 60 million Ib
(U.S. EPA (1979)) .*
All the methylaraines are used primarily as intermediates for
chemicals used in medicine, pesticides, rubber vulcanization, and
leather processing.
Some examples of compounds synthesized from methylamines
follow. Monomethylamine is a starting material for N-oleyltaurine,
a surfactant, and p-N-methylaminophenolsulfate, a photographic
developer. It has possible uses in solvent extraction systems in
the separation of aromatics from aliphatic hydrocarbons.
About half the dimethylamine produced is used to make di-
me thy If ormamide and dimethylacetamide, spinning solvents for acrylic
fibers. Dimethylamine is also used in the manufacture of lauryl-
methylamine, a surfactant, thiuram derivatives, which are used as
rubber accelerators, and 1,1-dimethylhydrazine, used as a rocket
fuel. Its sulfate salt is used in leather processing to dehair
hides.
Trimethylamine is used as a raw material in the production of
choline, a poultry feed additive, and as a polymerization catalyst
(Harwood, 1971; SRI, 1979).
Figures 1, 2, and 3 indicate additional general uses and
potential exposure to methylamines. MITRE Corp. (1976) calculated
that 20.6 million Ib each of DMA and TMA are released annually to
the environment.
Health Aspects
Acute Effects
In humans, methylamines are irritating to the lungs, eyes, and
upper respiratory tract at concentrations of 20-100 ppm (Sutton,
1963). These compounds have a pungent ammoniacal odor; human
olfactory thresholds are well below levels which produce irritation.
*This production range information does not include any production/
importation data claimed as confidential by the person(s) reporting
for the TSCA Inventory, nor does it include any information which
would compromise Confidential Business Information. The data sub-
mitted for the TSCA Inventory, including production range informa-
tion, are subject to the limitation contained in the Inventory
Reporting Regulations (40 CFR 710).
200
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The olfactory threshold values (ppb) for the methylamines
are monomethylamines, 2D; dimethylamines 23.2 or 47; and
trimethylamines 0.2 (Mitre Corp., 1976a).
In an acute study on rats, Dzhanashvili (1967) showed that
some of the acute effects of DMA, such as irritation of the mucous
membranes and stomach hemorrhages, were due to its basicity.
Chronic Effects
Most of the chronic studies available concentrated on dimeth-
ylamine, largely due to the potential for dimethylnitrosamine
formation. There is little toxicological information available
concerning monomethylamine or trimethylamine. A number of studies
attempt to determine whether nitrosamines are formed after concur-
rent administration of methylamine and nitrite and, if so, whether
the nitrosamine formed is carcinogenic.
Three subchronic studies in which animals were exposed to DMA
showed that DMA induced relatively minor toxicological changes. In
an 8-month study, 3.5 mg/kg DMA was fed to guinea pigs. The only
changes noted were an increase in the liver weight and a decrease
in phagocytic activity (Dzhanashvili, 1967). Rats, guinea pigs,
rabbits, dogs, and monkeys were exposed to 9 mg/m^ for 90 days via
inhalation. The author concludes that the animals showed no signs
of toxicity; all hematologic values were normal, but some rabbits
and monkeys did show dilation of the bronchi (Coon et al., 1970).
Isakova et al. (1971) report that rats exposed to 0.5 or 1 mg/m^
DMA for 3 months had significant increases at both concentrations
in the number of cells having an abnormal number of chromosomes.
There was a normal incidence of structural chromosome breakage,
however.
Like other alkylamines, dimethylamine may become nitrosated at
an appropriate pH level. Ishiwata et. al. (1975) reported that
dimethylnitrosamine (DMNA) was formed in human saliva cultivated
with DMA, nitrite, and glucose for 24 hr. Thus in vivo formation
of DMNA is a real possibility in humans.
Dimethylnitrosamine administered orally at 2 ppm induced
tumors in nearly all the rats after 60 weeks. In a 78-day study,
rats were exposed orally to nitrite (up to 5 g/1) and DMA (up to 4
cc/1). No tumors were observed, but there were some skin and eye
irregularities which the author explained by the depressed vitamin
A level in the liver. In a longer experiment, the nitrite levels
were increased to 30 g/1. Some rats in the high-nitrite group died
of methemoglobinemia, had a similar skin disorder, and had no
tumors. The rats in the 5-g/l nitrite group were slaughtered after
410 days and also had low liver vitamin A levels. Two had liver
tumors; one had a very large tumor and additional tumors in the
spleen and mesentery. The author concluded that: all tumors were
metastatic sarcomas and not cancers. None of the controls devel-
oped tumors (Oka et al., 1974). Epstein (1972) did a similar set
of experiments in which he fed various doses of nitrites and DMA
concurrently to mice. At 100 mg/kg nitrite and 2,500 mg/kg DMA,
centrilobular necrosis, similar to that induced by the administra-
tion of DMNA alone, was observed. Exposure to DMA alone had no
204
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toxic effects, and liver toxicity was reduced when two com-
pounds were consumed sequentially. The combination of nitrite and
DMA also inhibited the synthesis of liver protein in a dose-
dependent manner.
In a host-mediated assay using mice and Salmonella, DMA (via
oral gavage) and nitrite (per os) increased the mutation rate by a
factor of four. This increase is significant, though comparatively
modest. For each compound alone, water served as control (Couch
and Friedman, 1975) . In the only reference concerned with mono-
methylamine and nitrite, Hussain and Ehrenberg (1974) report that
the combination is mutagenic to E_. coli. Neither is mutagenic
alone.
Environmental Aspects
Great efforts have been expended to measure environmental
levels of methylamines and nitrosamines. Although methylamines
occur both naturally and as a result of manufacturing activities,
it has proven extremely difficult to determine if there is any
health hazard involved in environmental formation of nitrosamines.
Recent technological advances have made it possible to measure
nitrosamine concentrations at ppb levels; again, the significance
of exposure to these low levels is not clear.
Air
An article from industry points out that since methylamines
have such a disagreeable odor, scrubbers are used to remove the
methylamines from the stack effluents. Thus emissions are probably
minimal (Painst, 1961).
Fine (1976) measured DMNA levels in Belle, W. Va., site of
several amine plants, as 5-170 ng/m^ and in Baltimore as 3-320
ng/m^. Near a 1,1-dimethylhydrazine plant in Baltimore he found a
high of 36 x 103 ng/m3; it was later determined that there was a
DMNA source on the site. Fine concluded that DMNA may be a low-
level impurity of DMA.
Hanst (1977) conducted air chamber studies in which he demon-
strated that the rate of nitrosation of DMA in air is too slow to
allow for a buildup of DMNA. DMNA decomposes rapidly in UV light;
its half-life in sunlight is 30 min, so there is little likelihood
that DMNA is a daytime air pollutant. Degradation products from
the photolysis of DMNA include formaldehyde, formic acid, DMA, MMA,
and methylhydrazine (Grilli et al., 1975). However, DMNA formation
may occur at night, especially in polluted (NOX) air. Hanst con-
cluded that any DMNA in air is probably due to direct emissions.
An unpublished EPA study (Cohen and Bachman, 1977) concurs with
Hanst's conclusion that DMNA is not formed in the air. Samples of
industrial wastewater contained DMNA; it is not clear whether DMNA
was formed during manufacture or was present in the water supply.
205
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Soil
Tate 'and Alexander (1974) demonstrated that commercial concen-
trations of the pesticide dimethyldithiocarbamate degrade to DMA.
Traces of DMNA have been found after application of the pesticide.
Dean-Raymond and Alexander (1976) reported that DMNA can enter the
food chain due to its mobility in soil and ability to move through
the roots to the leaves of spinach and lettuce. The authors note
that there is also a potential for accumulation in ground water.
Several experimenters have demonstrated that nitrites and TMA
or DMA form DMNA in soils and manures. However, the concentrations
required are high, and no DMNA has been found naturally in soils,
sewage, or lake water (Mills and Alexander, 1976; Ayanaba and
Alexander, 1974; Tate and Alexander, 1976).
Other
A brief summary of other areas in which methylamines have been
found follows. Methylamines are known to be present in fish. On a
fully loaded fish boat, a TMA concentration of 59 ppm was measured;
men unloading the fish often felt uncomfortable and some fainted
(Daalgard et al., 1972). TMA (at 5 ppm) is responsible for the
undesirable fishy taste in milk (Von Gunten, 1976). All the
methylamines have been detected in cattle feed yards and in faci-
lities using liquid manure (Mosier and Torbit, 1976).
Perhaps the best known example of nitrosamine formation is in
treated meats such as bacon, ham, and frankfurters. Nitrite is
used to cure these meats, but, on cooking, measurable amounts (high
of 39 ppb) of dimethylnitrosamine are formed in bacon (Wasserman et
al., 1978; Collins and MacDonald, 1978). It is not known exactly
which amines are the precursors to the nitrosamines.
REFERENCES
Ayanaba, J., and M. Alexander. Transformations of methylamines
and formation of a hazardous product, dimethylnitrosamine,
in samples of treated sewage and lake water. Environ. Qual.
3_(1) :83, 1974.
Cohen and Bachman. Measurement of Environmental Nitrosamines.
Unpublished paper. 1977.
Coon, R. A., R. A. Jones, L. J. Jenkins, and J. Siegel. Animal
inhalation studies on ammonia, ethylene glycol, formaldehyde,
dimethylamine, and ethanol. Toxicol. Appl. Pharmacol.
16_:646, 1970.
Couch, D. B., and M. A. Friedman. Interactive mutagenicity of
sodium nitrite, dimethylamine, methyl urea, and ethyl urea.
Mutat. Res. 3_1:109, 1975.
206
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Daalgard, J. B., F. Denker et al. Fatal poisoning and other health
hazards connected with industrial fishing. Br. J. Ind. Med.
:307, 1972.
Dean -Raymond, D. , and M. Alexander. Plant uptake and leaching of
dimethylnitrosamine. Nature 262 (5567) ;394, 1976.
Dzhanashvili, G. D. Hygiene substantiation of the maximum permis-
sible content of dimethylamine in water bodies. Gig. Sanit.
3_7_(6) :12, 1967.
Epstein, S. S. In vivo studies on interactions between secondary
amines and nitrites or nitrates. Anal. Form. Proc. Work Conf.
(IARC) . 1972. p. 109-115.
Fine, D. H. , D. P. Rounbehler et al. N-nitrosodimethylamine in
air. Bull. Environ. Contam. Toxicol. lj[(6):739, 1976.
Gray, J. I., M. E. Collins, and B. MacDonald. Precursors to dimethyl-
nitrosamine in bacon. J. Food. Prot. £1(1) :31, 1978.
Grilli, S., M. R. Tosi, and G. Prodi. Degradation of dimethylnitro-
samine catalysed by physical and chemical agents. Gann
:481, 1975.
Hanst, P. L., J. W. Spence, and M. Miller. Atmospheric chemistry
of N-nitrosodimethylamine. Environ. Sci. Technol. 11 (4) ; 403,
1977.
Harwood, H. J. Amines, lower aliphatic. In_ Kirk-Othmer Encyclo-
pedia of Chemical Technology, vol. 2. New York, John Wiley &
Sons, Inc. 1971. p. 116.
Hussain, S., and L. Ehrenberg. Mutagenicity of primary amines
combined with nitrite. Mutat. Res. ^(5):419, 1974.
Isakova, G. K. , B. Y. Ekshtat, and Y. Y. Kerkis. On studies of
the mutagenic properties of chemical substances in the estab-
lishment of hygienic standards. Gig. Sanit. 36J11) :9, 1971.
Ishiwata, H. , A. Tanimura, and M. Ishidate. Studies on in vivo
formation of nitroso compounds. V. Formation of dimethyl-
nitrosamine from nitrate and dimethylamine by bacteria in
human saliva. Food Hyg. Soc. Jpn. 16_(4):234, 1975.
Mills, A. L., and M. Alexander. Factors affecting dimethylnitros-
amine formation in samples of soil and water. J. Environ.
Qual. 5_(4) :437, 1976.
MITRE Corp. Environmental Aspects of Atmospheric Nitrosamines.
1976. a
207
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MITRE Corp. Scoring of Organic Air Pollutants. 1976.b*
Hosier, A. R., and S. Torbit. Synthesis and stability of dimethyl-
nitrosamine in cattle manure. J. Environ. Qual. 5^(4) :465,
1976.
Oka, K., K. Betto, and I. Nishimori. Development of sarcomata in
the livers of albino rats given sodium nitrate and dimethyl-
amine. Acta Med. Nagasaki 1£(1-4):13, 1974.
Paist, S. S. Air pollution and methylamines. Ind. Water Wastes
6_:158, 1961.
Stanford Research Institute (SRI). Chemical Economics Handbook.
Menlo Park, Calif. 1975.
Button, W. L. Aliphatic and alicyclic amines. In. F- A. Patty
(ed.), Industrial Hygiene and Toxicology, 2nd ed. New York,
Interscience Publishers. 1963.
Tate, R. L., and M. Alexander. Formation of dimethylamine and
diethylamine in soil treated with pesticides. Soil Sci.
118(5):317, 1974.
Tate, R. L., and M. Alexander. Microbial formation and degradation
of dimethylamine. Appl. Environ. Microbiol. 31(3);399,
1976.
U.S. EPA (1979), Toxic Substances Control Act Chemical Substance
Inventory, Office of Toxic Substances, Washington, B.C.
U.S. International Trade Commission (U.S. ITC). Synthetic Organic
Chemicals, United States Production and Sales, 1975.
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some informa-
tion is not possible. The environmental release data were taken
from the NSF/Rann Research Program on Hazard Priority Ranking of
Manufactured Chemicals.
208
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CHEMICAL HAZARD INFORMATION PROFILE
Morpholine
Date of report: November 16, 1977
This chemical was chosen for study because of the exposure
potential associated with its use as a boiler water additive.
The following recommendations are made regarding further OTE
evaluation of the possible health or environmental hazards of
morpholine.
(1) Require TSCA Section 8(a) submissions—Detailed infor-
mation on production and uses is not currently available,
(2) Require TSCA Section 8(d) submissions—Available infor-
mation does not provide very extensive coverage of the
health aspects of morpholine.
(3) Revise CHIP report and repeat review.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Morpholine, OCH2-CH2-NHCH2-CH2 (molecular weight, 87.14), is
a colorless, volatile, alkaline, hygroscopic liquid with an amine-
like odor. It is miscible with water (some heat is evolved), but
does not form a morpholine/water azeotrope. Morpholine is also
very soluble in acetone, benzene, ether, methanol, ethanol, and
numerous other solvents. Morpholine melts at -4.9°C and boils at
128.9°C. It has a density of 1.002 g/ml at 20°C. The flash point
of morpholine is 38°C (100°F) by the open-cup method. Morpholine
is flammable and a moderate fire risk.
Synonyms for morpholine include diethylene oximide, diethylene
imidoxide, and tetrahydro-1,4-oxazine. Morpholine undergoes
reactions typical of a secondary amine. Morpholine's desirable
characteristics include reactivity (which is enhanced by the ring
structure), mild alkalinity, good solvent properties (due, in
part, to the ether oxygen), and a medium boiling point.
209
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Production and Use
Morpholine annual production capacity is 15 million Ib. The
producer is Jefferson Chemical Co. (a subsidiary of Texaco Inc.).
Dow has had a 5 million Ib/year plant on standby since mid-1972.
Union Carbide was scheduled to shut down their 15 million Ib/year
plant at the end of 1974. The demand for morpholine was 24 million
Ib/year in both 1973 and 1974. In 1974 the price was 65§ per
pound delivered in tanks in the East.
Morpholine can be made by reaction of ethylene oxide and
ammonia (Hawley, 1977). Other established manufacturing methods
are (1) by dehydration of diethanolamine, (2) by reaction of
diethylene glycol with ammonia in the presence of hydrogen, an
appropriate catalyst, and high temperature and pressure, and (3)
by heating bis(2-chloroethyl)ether and anhydrous ammonia in benzene
solution in a closed vessel at 50°C for 24 hr (Kirk-Othmer,
1967).
Morpholine is used in rubber chemicals (especially accelerators)
33%; corrosion inhibitors, 25%; optical brighteners for detergents,
10%; alkyl morpholines, 10%; waxes, polishes, and cleaners, 8%;
exports, 7%; and miscellaneous, 7%.
Specific applications implied by these categories include use
of morpholine as a solvent, use in organic synthesis (especially
of Pharmaceuticals), use as a boiler water additive, and use in
the preservation of book paper (Chemical Marketing Reporter,
1974; Hawley, 1977). Morpholine salts of fatty acids may be used
as a component of a protective coating applied to fruits and
vegetables (permitted under the Federal Food, Drug, and Cosmetic
Act) (Kirk-Othmer, 1967).
Health Aspects
The recommended TLV for morpholine is 20 ppm time weighted
average (70 mg/m^). Caution is often recommended because mor-
pholine can be absorbed through the skin. The single oral LDso
for rats is 1,050 mg/kg. The single dermal LDso ^or 24-hr skin
contact is 0.5 mg/kg. Oral administration of 6,330 mg/kg (total
dose) over 28 weeks of continuous administration causes neoplastic
effects and serves as the TDLo (ITU, 1976).
Investigations were conducted by Shea (as described in ACGIH,
1971) utilizing commercial-grade morpholine (98% pure) in inhalation
studies, on rats. The notable effects were nasal and bronchial
irritation and liver and kidney damage. Rats were exposed to
18,000 ppm for 8 hr daily. One animal died after the 1st day.
Its liver and kidney showed congestion and a cloudy swelling. All
exposed animals developed violently reddened thoracic walls. A
second rat died the 3rd day from lung and kidney congestion. A
third rat died on day 4, showing degeneration of the epithelial
lining of the kidney tubules. Three rats died after termination
of exposure on day 5.
210
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Thickened alveoli, emphysematous areas, incipient necrosis of
kidneys and areas of degeneration, fatty changes, and cellular
necrosis of the liver were noted. When Shea (reference unknown)
was exposed to 12,000 ppm morpholine, he noted nose irritation
after 1 min and coughing after 1.5 min. The transfer of morpholine
by pipette caused a severe sore throat and reddened mucous membranes.
These symptoms cleared upon cessation of this experiment.
Environmental Aspects
It is estimated that the fraction of dispersion of morpholine
is 0.50; an additional 0.03 is lost in production. Thus an estimated
53% of morpholine produced is dispersed (12.4 million Ib/year if
production is estimated at 23.3 million Ib/year) (Dorigan et al.,
1976).
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists).
Documentation of TLV's. 1971.
Chemical Marketing Reporter. June 3, 1974.
Dorigan, J. et al. Scoring of Organic Air Pollutants. MITRE Corp.
1976.*
Hawley, G. G. (ed.). Condensed Chemical Dictionary, 9th ed. New
York, Van Nostrand Reinhold Co. 1977.
ITII (International Technical Information Institute). Toxic and
Hazardous Industrial Chemicals Safety Manual. Tokyo. 1976.
Kirk-Othmer Encyclopedia of Chemical Technology. New York, John
Wiley & Sons, Inc. 1967.
The Merck Index, 8th ed. Rahway, N.J., Merck and Co., Inc. 1963.
Sax, N. Irving (ed.). Dangerous Properties of Industrial Materials,
3rd ed. New York, Van Nostrand Reinhold Co. 1977.
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some informa-
tion is not possible. The environmental release data were taken
from NSF/Rann Research Program on Hazard Priority Ranking of
Manufacturing Chemicals.
211
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CHEMICAL HAZARD INFORMATION PROFILE
2-N itropropane
Date of report: September 27, 1977
This chemical was chosen for study because of carcinogenic
activity reported in a NIOSH Current Intelligence Bulletin.
It is recommended that 2-nitropropane proceed to a PRL I
assessment. Evidence of carcinogenicity in test animals and toxic
effects observed in workers exposed to 2-nitropropane imply that
it may present serious health problems. Requiring TSCA Section
8(a) and 8(d) submissions is recommended in order to provide a
better base of information for PRL I assessment.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
2-Nitropropane is a clear, colorless liquid with a pleasant
odor. Its molecular formula is CH3CH(N02)CH3. It has a molecular
weight of 89.09. Synonyms for 2-nitropropane include dimethylni-
tromethane, isonitropropane, nitroisopropane, and 2NP; it is
marketed under names such as NiPar S-20. The melting point of 2-
nitropropane is -93°C; the boiling point is 120.3°C. It is slightly
soluble in water (1.7 ml/100 ml of water at 25°C). Water is
soluble in 2-nitropropane (0.6 ml water/100 ml of 2NP). Nitropropane
dissolves in many solvents, including chloroform. The specific
gravity of 2-nitropropane is 0.992. Its vapor pressure is 20 mm
Hg at 25°C (13 mm Hg at 20°C). Its ignition temperature is 802°F
(Browning, 1965). Its vapors make for an explosive mixture with
air. The lower flammability limit is 2.6% by volume in air (upper
limit unknown). 2-Nitropropane exists in equilibrium with 2-
propane nitronic acid:
H CH3 CH3 CH3 CH3
cH3-c-cH3 —^ y —^ V
N* * +K * N
// \ A / \
o o- -o oH o-o
212
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At equilibrium one finds a much higher concentration of the true
nitro compound. 2-Nitropropane also exists as aci-2-nitropropane
(a derivative of the sodium salt).
Production and Use
The vapor-phase reaction between propane and nitric acid
vapor gives crude 2-nitropropane. The reaction is carried out at
370 to 450°C and 8 to 12 atmospheres pressure in stainless-steel
apparatus. The reaction products are cooled. The various nitro-
propanes and the associated by-products of aldehydes and ketones
condense while the nitric oxide and unreacted propane remain as
vapor. The propane is separated from the nitric oxide and recycled.
Nitric oxide is removed for conversion to air, water, and nitric
acid (which reenters the system). The crude 2-nitropropane is
washed and sent to fractionation towers for separation by dis-
tillation (Kirk-Othmer, 1967).
2-Nitropropane has been commercially available since 1940
from Commercial Solvents Corp., (recently acquired by IMC Corp.).
It is produced at their plant in Sterlington, La. Twelve million
of the estimated 30 million Ib of 2-nitropropane produced annually
is sold domestically; the remainder is either used internally at
IMC or exported (HEW/NIOSH, 1977). Major distributors of 2-
nitropropane (other than Commercial Solvents Corp.) include Amsco
Division of Union Oil Co. of California, Ashland Chemical Co.
(Industrial Chemicals and Solvents Division), and Thompson Hayward
Chemical Co. (Finklea, 1977).
2-Nitropropane is used in manufacturing as a solvent for
organic compounds, cellulose, esters, resins, gums, vinyl resins,
waxes, epoxy, fats, dyes, and chlorinated rubber. Desirable
qualities which 2-nitropropane contributes to solvent systems
include improved drying time, more complete solvent release,
better flow and film integrity, greater wetting ability, improved
electrostatic spraying, and increased pigment dispersion. It is
used as a solvent for printing on polyvinyl films. 2-Nitropropane
is utilized in the coating industry, where its use showed a rapid
increase at least up to the early 1960's. Its combustion prop-
erties have made it useful as a rocket propellant and as a gasoline
and diesel fuel additive. 2-Nitropropane also has limited use as
a paint and varnish remover. It serves as an intermediate in
organic synthesis of some Pharmaceuticals, dyes, insecticides, and
textile chemicals.
213
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Nitroparaffins have been used for fuels in model engines and
short-distance racing cars since at least the mid-1950's and up to
at least the mid-1960's. Such racing car fuels might contain 20%
2-nitropropane. 2-Nitropropane and 2,2-dinitropropane have been
tested as rocket propellants. 2-Nitropropane gives both desirable
physical properties and relative ease of handling and availability.
The addition of as little as 0.1 to 0.2% by weight of 2,2-dinitropropane
increases the octane rating of diesel fuel from 5 to 10 units.
Nitropropane is especially useful as a fuel additive when extra
power may be needed for short periods of time. It increases power
output and reduces the smoke coming from the exhaust. This has
important potential for air pollution abatement (Kirk-Othmer,
1967).
The major uses of 2-nitropropane as stated by sources at IMC
are as a solvent in industrial coatings and in printing inks. 2-
Nitropropane is used internally by IMC for conversion to nitro
compounds including aminohydroxy compounds. IMC also sells 2-
nitropropane abroad. (NIOSH estimates that 100,000 workers are
potentially exposed to 2-nitropropane [Finklea, 1977]. Sources at
IMC claim that a maximum of 15,000 persons are exposed.)
Health Aspects
General
The trend in the evaluation of the toxicity of 2-nitropropane
has been toward considering it as an increasingly dangerous sub-
stance. In 1962 the American Council of Governmental Industrial
Hygienists (ACGIH) recommended 50 ppm as the maximum acceptable
occupational exposure for 2-nitropropane. By 1971, this was
changed to 25 ppm, which is the current OSHA standard for occupa-
tional exposure. Based on their most recent studies, NIOSH cur-
rently recommends handling 2-nitropropane as if it were a
carcinogen (Finklea, 1977).
The TLM aquatic toxicity rating for 2-nitropropane (96-
hr exposure) is 10-100 ppm; this is considered a "slightly
toxic" rating (NIOSH, 1976).
Humans (General)
Generally observed symptoms in humans exposed to 2-nitro-
propane vapors include anorexia, nausea, vomiting, diarrhea,
severe occipital headaches, cyanosis, and vapor irritation of the
lungs. Large doses have the potential of producing methemoglobinemia
and damaging the liver and kidneys. Other toxic effects on the
central nervous system may arise. 2-Nitropropane cannot be detected
in humans by odor at 83 ppm (Sutton, 1963).
214
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Human Exposure
There are report sources that five or six workers dipping
forms into a solvent mixture of vinyl copolymer dissolved in
xylene and ^20% 2-nitropropane (at 110 to 120°F and occasionally
150°F) developed anorexia, nausea, vomiting, and occasional diarrhea.
Symptoms were not present before exposure, but would arise as the
workday progressed. Workers had no symptoms on holidays. The
exposure level in the work area was approximately 20 to 45 ppm of
2-nitropropane (no xylene concentration given). Substitution of
methyl ethyl ketone relieved the symptoms (Browning, 1965).
Workers exposed to concentrations of 10 to 30 ppm of 2-
nitropropane for not more than 4 hr per day, 3 days per week, in a
spraying operation (utilizing lacquer with 20% 2-nitropropane)
experienced no ill effects (Sutton, 1963).
A report source on two workers attributes the death of one,
and liver damage in both, to high-level exposure to 2-nitropropane
while painting the inside of a tank (Finklea, 1977, refers to
Gaultier et al., Arch. Mai. Prof. 25^:425, 1964).
In another report source, workers exposed to from 165 to 445
ppm mixed 1- and 2-nitropropane experienced nausea, dizziness,
headaches, and diarrhea (Finklea, 1977, refers to Documentation of
Threshold Limit Values, American Conference of Governmental
Industrial Hygienists, 1971).
Williams et al. (1974) reported an excess of toxic hepatitis
among construction workers applying epoxy resins to the walls of a
nuclear power plant. Although the hepatitis in this case was
attributed to exposure to a known hepatotoxin, p,p'-methylene-
dianiline, these men had also used 2-nitropropane to remove hardened
resin from their skin (Finklea, 1977).
Animals
The primary route of absorption of nitroparaffins (including
2-nitropropane) is through the lungs and the gastrointestinal
tract; no symptom-producing absorption is known to occur through
the skin. Mononitroparaffins disappear from the blood rapidly
after absorption. A portion is excreted unchanged in expired air,
and, a portion is metabolized with resulting formation of N02~ and
NC>3~ (found in blood and urine) . The overall reaction iji vivo
appears to be:
N02
215
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Lethal dosage depends on concentration and length of exposure.
Studies have been done on measured exposure to 2-nitropropane
using monkeys, cats, rabbits, rats, and guinea pigs. Experimentally,
cats were most sensitive to 2-nitropropane; guinea pigs were least
sensitive. Exposure to high concentrations of 2-nitropropane
caused dyspnea, cyanosis, prostration, some convulsions, lethargy,
and weakness, proceeding to coma and death. In cats and rats,
coma and death followed in a short time, while rabbits and guinea
pigs died 1 to 4 days after apparent partial recovery. Severe
exposure caused 60 to 80% methemoglobin in cats., Heinz body
formation was also more frequent in cats. Exposure of cats to 328
ppm caused prothrombin reduction and increased clotting time.
Livers of cats that died after exposure to several periods of 328
ppm showed severe degeneration and focal necrosis. Cats exposed
to 328 ppm 2-nitropropane showed degeneration in heart and kidneys
and cerebral neuron disintegration. The lungs showed pulmonary
edema, intraalveolar hemorrhage, and interpneumonitis. Other
species exposed to this concentration did not exhibit these symptoms.
Cats developed 25 to 35% methemoglobin when exposed to 750 ppm for
4.5 hr; they showed 15 to 25% methemoglobin when repeatedly exposed
to 280 ppm for 7 hr per day. Heinz bodies appeared in the erythro-
cytes of cats and rabbits at even lower concentrations (Browning,
1965) .
The most recent studies on the effects of 2-nitropropane
inhalation were conducted by the Huntingdon Research Center for
NIOSH (HEW/NIOSH, 1977). It involved exposing rats and rabbits to
commercial-grade 2-nitropropane for 7 hr per day, 5 days per week.
One group was exposed to 207 ppm 2-nitropropane; a second group was
exposed to 27 ppm; a third group was as a control. The rats exposed
to 207 ppm 2-nitropropane were weanling rats (younger and smaller
than the other exposed rats and the control group). They were
introduced to replace rats experiencing excess mortality during the
first few days of exposure to 400 ppm 2-nitropropane. Also, food and
water were present during exposure in all cases, adding the potential
for oral intake of 2-nitropropane (Finklea, 1977). Animals were
killed at intervals in order to evaluate the effects of 2-nitro-
propane exposure. Liver neoplasms, described as hepatocellular
carcinoma or hepatic adenoma, were observed in all rats killed after
6 months of exposure to 207 ppm 2-nitropropane. No tumors were
observed in any other animals in this study, including controls.
Further investigation of the toxicity of 2-nitropropane was begun in
April 1977 under the sponsorship of the IMC Chemical Group, Inc.
(Finklea, 1977).
Specific Related Compounds
1-Nitropropane is an isomer of 2-nitropropane. 2,2-Dinitro-
propane is made by liquid-phase nitration of propane. The greater
the number of nitro groups (or unsaturation), the greater the
irritant effect. l-Chloro-2-nitropropane is used as a soil
fungicide. (Federal Register, 1971). 2-Chloro-l-nitropropane
has been found useful in starfish control.
216
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Environmental Aspects
No information was found in the sources consulted on
the environmental fate or effects of 2-nitropropane.
REFERENCES
Browning, Ethel. Toxicity and Metabolism of Industrial Solvents.
New York, Elsevier Publishing Co. 1965. p. 283-284.
Federal Register, Rules and Regulations, Part 420, Tolerances and
Exemptions from Tolerances for Pesticide Chemicals in or on
Raw Agricultural Commodities, l-Chloro-2-Nitropropane.
Series 36, issue 175, Sept. 9, 1971, p. 18079-18080.
Finklea, John F. Current Intelligence Bulletin: 2-Nitropropane.
National Institute for Occupational Safety and Health. April
25, 1977.
Hawley, G. G. (ed.). The Condensed Chemical Dictionary, 9th ed.
New York, Van Nostrand Reinhold Co. 1977.
HEW/NIOSH (1977), Chronic Inhalation Exposure of Rats and Rabbits
to Nitromethane and 2-Nitropropane, Project No. 210-75-0039.
International Technical Information Institute. Toxic and Hazardous
Industrial Chemicals Safety Manual. Tokyo. 1976. p. 377-
378.
Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed., vol. 13.
New York, John Wiley & Sons, Inc. 1976. p. 864-883.
The Merck Index, 8th ed. Rahway, N.J., Merck and Co., Inc. 1968.
NIOSH. Registry of Toxic Effects of Chemical Substances, 1976 ed.
Sax, Irving N. Dangerous Properties of Industrial Materials, 3rd
ed. New York, Van Nostrand Reinhold Co. 1968.
Steere, Norman V. Hazardous chemicals data. J. Chem. Educ.
4_5(4) :A317-A318, 1968.
Sutton, William L. Aliphatic nitro compounds, nitrates, and
nitrites. In Frank A. Patty (ed.), Industrial Hygiene and
Toxicology, 2nd ed., vol. 2. New York, Interscience Publishers,
Inc. 1963. p. 200 1-2079.
Weast, Robert C. (ed.). CRC Handbook of Chemistry and Physics,
52nd ed. Cleveland, The Chemical Rubber Co. 1971.
Williams, S. V. et al. Toxic hepatitis and methylenedianiline.
N. Engl. J. Med. 29^:265, 1974.
217
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CHEMICAL HAZARD INFORMATION PROFILE
2-Pentanone
Date of report: December 6, 1977
This chemical was chosen for study because of an inquiry
about its possible occurrence in a drinking water supply.
No judgment on this chemical is appropriate at this time
because of a lack of information.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may not reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Chemical Identity
2-Pentanone (CsHiQO) is a clear liquid with a strong odor
resembling acetone and ether. It melts at -83.5°C and boils at
102°C. The vapor pressure of 2-pentanone is 16 mm Hg at 20°C; its
specific gravity is 0.8064 (at 20°C). It is soluble in acetone
and in ether and is slightly soluble in water (5.5 g/100 g). 2-
Pentanone is flammable from 1.55% to 8.15% by volume in air.
Synonyms for 2-pentanone include methyl n-propyl ketone, ethyl
acetone, and methyl propyl ketone. (Browning 1.965; Patty 1963).
Production and Use
The major method of production of 2-pentanone is by oxidation
of 2-pentanol. 2-Pentanone is used as a solvent, especially as a
substitute for diethyl ketone. It is used as a solvent in much
the same places that acetone is used. 2-Pentanone has also been
used as a flavoring (Hawley, 1977). (It has been approved for use
as a synthetic flavoring by the FDA [Title 21, 172.515, Code of
Federal Regulations].) It is produced by Union Carbide Corp. in
West Virginia (SRI, 1975). Due to the fact that there is only one
commercial producer of 2-pentanone, no information on production
volume or capacity is available.
218
-------
Health Aspects
The TLV of 2-pentanone is 200 ppm (ACGIH, 1971). The LD^g for
oral administration to rats is 3,730 mg/kg. The 4-hr inhalation
LCso is 2,000 ppm for rats (NIOSH, 1976). 2-Pentanone vapors
irritate the eyes and respiratory tract. At high concentrations it
acts as a narcotic (ITII, 1976). No toxic effects have been reported
from industrial use.
Absorption through the skin has been observed with 2-pentanone.
Elimination takes place mainly unchanged in expired air (estimated 38
to 54% expelled in air in 25 to 35 hr). The rate of elimination of
2-pentanone from the blood is only half as fast as that of 2-pen-
tanol. 2-Pentanone may be excreted in combination with glucuronic
acid. 2-Pentanone is the major metabolite of 2-pentanol (Browning,
1965). No references were found pertaining to the mutagenicity or
carcinogenicity of 2-pentanone.
Environmental Aspects
No information was found on environmental aspects of 2-
pentanone.
REFERENCES
American Conference of Governmental Industrial Hygienists
(ACGIH). Documentation of TLV's. 1971.
Browning, Ethel. Toxicity and Metabolism of Industrial
Solvents. Amsterdam, Elsevier Publishing Co. 1965.
Hawley, G. G. (ed.). Condensed Chemical Dictionary, 9th
ed. New York, Van Nostrand Reinhold Co. 1977.
ITII (International Technical Information Institute).
Toxic and Hazardous Industrial Chemicals Safety
Manual. Tokyo. 1976.
NIOSH. Registry of Toxic Effects of Chemical Substances,
1976 ed.
Patty, Frank A. (ed.). Industrial Hygiene and Toxicology.
New York, Interscience Publishers, Inc. 1963.
SRI (Stanford Research Institute). Directory of Chemical
Producers. Menlo Park, Calif. 1975.
219
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CHEMICAL HAZARD INFORMATION PROFILE
Phenylenediamines
Date of report: June 1, 1978
This group of chemicals was chosen for study because of the
exposure potential associated with its use pattern and the struc-
tural relationship of these chemicals to known carcinogens.
It is recommended that judgment be deferred on phenylenedia-
mines due to insufficient information. Additional information
which should be obtained before making a judgment includes:
(1) Results of NCI carcinogenicity study.
(2) Production volume from TSCA inventory.
(3) Use information through Section 8(a).
(4) Relevant information obtained by the Interagency
Testing Committee in its review of these compounds.
(5) Update this CHIP based upon the additional information
obtained.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
There are three isomers of phenylenediamine, the ortho, meta,
and para forms. All the isomers are crystalline solids at room
temperature and are soluble in water, alcohol, ether, and benzene.
220
-------
CAS
no.
Chemical
name
Melting pt. Vapor
(°C) pressure Log P
95-54-5
108-45-2
100-50-3
Ortho-phenylene-
diamine (o-PDA)
Meta-phenylene-
diamine (m-PDA)
Para-phenylene-
diamine (p-PDA)
102
65
140
Neg.
.37
1 mm Hg/
98.8°C
.26
Source: Adapted from Weast, 1971, and MITRE Corp., 1976.
Production and Use
This section is based largely on information compiled by
Auerbach Associates.
Current production data are not available for phenylenedia-
mines. In 1962, 540,000 Ib of o-PDA and 1.4 million Ib of m-PDA
were produced (Kirk-Othmer, 1968). SRI (1977) lists the annual
production of each phenylenediamine as over 1,000 Ib. Although
production volume appears to be limited, there are 10 manufacturers
and processors, and the uses indicate a potential for human exposure.
General uses for phenylenediamines include applications as dye
intermediates, as oxidation inhibitors in petroleum and rubber
products, and as photographic developers. The three compounds are
found in a variety of oxidative hair dyes and are also used in
dyeing furs. Miscellaneous uses for each compound are listed
below:
o-PDA Lab reagent
m-PDA Textile developing agent, corrosion inhibitor,
monomer for Nomex Nylon, used in fire-resis-
tant clothing, prepolymer for spandex
p-PDA Ursol, a fur dye, monomer in Fiber B to make
tire cord
Source: SRI, 1975; Kirk-Othmer, 1968.
Health Aspects
The major issues involved are centered around the use of
phenylenediamines in consumer hair dyes. Many hair dyes are
mutagens in the Ames system. Long-term industry studies have
failed to demonstrate that there is a risk of either cancer or
chromosome damage associated with hair dyes. However, most of
these studies attempt to replicate patterns of human exposure to
hair dyes in rats. Another area of concern is skin sensitization,
221
-------
Acute Effects
Although phenylenediamines are fairly toxic when administered
subcutaneously, neither m-PDA or p-PDA is very fat soluble and
would not normally be expected to enter the body. There are no
known cases of industrial poisoning (Hamblin, 1963) .
LDLo - Subcutaneous - rat o-PDA 600 mg/kg
m-PDA 80 mg/kg
p-PDA 100 mg/kg
Source: NIOSH, 1975.
Skin Sensitization
p-PDA is easily oxidized in air and moisture, and these
oxidation products are strong skin sensitizers. Industrial
exposure has caused allergic bronchial asthma. Because of skin
sensitization, the TLV for p-PDA is 0.01 mg/m3 (ACGIH, 1971).
Two epidemiological surveys indicate that p-PDA is one of the
most common skin sensitizers. Using skin allergy patients as
subjects, 8% of 1,200 patients reacted to a 1% p-PDA solution in a
standard skin patch test. In the other study, a 2% solution of p-
PDA induced allergic reactions in 13.5% of the subjects. In
addition, there was a strong cross-sensitization to substituted
phenylenediamines such as isopropyl-PDA, which is used in rubber
and tires (Baer et al., 1973; Rudner et al., 1973). Fisher (1975)
studied 20 patients who were strongly sensitized to p-PDA to
determine whether they were allergic to hair dyed with p-PDA.
None of the patients reacted to the dyed hair.
Mutagenicity and Chronic Studies
Ames (1975) tested 169 hair dyes and found that 150
were mutagenic in his assay. Some required microsomal activation
and others required oxidation with hydrogen peroxide. Both o-PDA
and m-PDA were mutagenic in a dose-dependent manner in Salmonella
strain TA 1538, which detects frameshift mutagens. The para
isomer alone was not mutagenic in a variety of Salmonella strains.
However, when oxidized with peroxide, a highly mutagenic trimer
was formed. Under normal hair-dyeing conditions, this reaction
product is thought to be a minor constituent, but it can be
absorbed through dog's skin. Garner and Nutman (1977) report that
all three phenylenediamines are dose-related mutagens in the Ames
system with liver activation. The m-PPA caused a 50-fold increase
in the spontaneous mutation rate of mouse lymphoma cells (Palmer
et al., 1977). Blijleven (1977) found that p-PDA alone is a weak
mutagen in Drosophila melanogaster. The three compounds were
administered orally to males and induced mutations in metaboli-
cally active germ cells. Burnett et al. (1977) conducted a
dominant lethal assay on rats. Male rats were given 20 mg/kg of
222
-------
o-, m-, or p-PDA intraperitoneally three times a week for 8 weeks.
After a brief waiting period they were allowed to mate. The
investigators found no statistically significant changes in the
numbers of resorptions or live fetuses.
Burnett et al. (1976) found that hair dye which contained 2%
p-PDA was not teratogenic to rabbits. Other active ingredients
were resorcinol, 2,4-diaminoanisole sulfate, and 2-nitrophenyl-
enediamine. Hair dyes were mixed with peroxide according to
directions and were applied to the skin twice a week for 13 weeks.
There was no evidence of teratogenicity, systemic toxicity, or
lesions; organ weights and blood values were normal. Nine out of
169 fetuses did have abnormalities such as notched or short ribs.
In another study (Burnett et al., 1975), hair dye containing p-PDA
and m-PDA was applied to mouse skin weekly or biweekly for 18
months. Again, no evidence of carcinogenicity or blood or organ
abnormalities was found.
Giles and Chung (1976) conducted a 2-year mouse skin-painting
study using 2,4-toluenediamine alone and in combination with p-
PDA, resorcinol, and 2,5-TDA. There was a high spontaneous rate
of skin and lung neoplasms (15%), and the authors concluded that
the treated groups did not have significantly more neoplasms than
the controls.
Russian experimenters (Kachalai et al., 1973) found that m-
PDA administered orally to rats for 3 to 4 months affected the
central nervous system and the detoxification activity of the
liver. When applied to the rats' skin, it induced dermatitis.
Human subjects exposed to 1 to 2 yg/1 (route and duration not
stated) developed pathological liver and kidney changes.
NCI has completed a bioassay on the hydrochloride salt of p-
phenylenediamine and is drafting a report.
Environmental Aspects
No information was found concerning the environmental aspects
of phenylenediamines. Since they are easily oxidized, they would
not be expected to persist in the air or water. Their low parti-
tion coefficients indicate little potential for bioaccumulation.
SUPPLEMENT
Very little information was available concerning phenylenetria-
mines; instead of writing a separate profile, this supplements the
profile of phenylenediamines.
Chemical Identity
The melting point of 1,2,3-phenylenetriamine is 103°C and it
is soluble in water, alcohol, and ether (Weast, 1971).
223
-------
Production and Use
It appears that 1,3,5-triaminobenzene may be the only isomer
of commercial importance; however, production figures were not
available. It is primarily used as an intermediate in the produc-
tion of phloroglucinol (1,3,5-trihydroxybenzene), which is used in
the dye and reproduction process industries. Other applications
include use as an ion exchange resin intermediate, as a photo-
graphic developer (CCD, 1971; Kirk-Othmer, 1968), and as a wetting
and frothing agent.
Health Aspects
Garner and Nutman (1977) reported that after liver activation
1,2,4-triaminobenzene is a strong mutagen in S. typhimurium TA
1538, which detects frameshift mutations. This compound is a
possible degradation product of chrysoidine, an azo dye known as
Basic Orange 2, which is a mouse carcinogen.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists).
Documentation of Threshold Limit Values. Cincinnati. 1971.
Ames, B. A., H. D. Kammen, and E. Yamasaki. Hair dyes are muta-
genic: Identification of a variety of mutagenic ingredients.
Proc. Natl. Acad. Sci. U.S.A. ;72(b):2423, 1975.
Baer, R. L., D. L. Ramsey, and E. Biondi. The most common contact
allergens. Arch. Dermatol. 108;74, 1973.
Blijleven, W. G. H. Mutagenicity of four hair dyes in Drosophila
melanogaster. Mutat. Res. 4_8_:181, 1977.
Burnett, C., E. I. Goldenthal et al. Teratology and percutaneous
toxicity studies on hair dyes. J. Toxicol., Environ. Health
3^1027, 1976.
Burnett, C., B. Lanman et al. Long-term toxicity studies on oxi-
dation hair dyes. Food Cosmet. Toxicol. 13_:353, 1975.
Burnett, C., R. Loehr, and J. Corbett. Dominant lethal mutageni-
city study on hair dyes. J. Toxicol. Environ. Health 2^657,
1977.
Chemical Week (October 1977), 1978 Buyer's Guide Issue, Part 2, p.
550.
Condensed Chemical Dictionary (CCD), 8th ed. New York, Van
Nostrand Reinhold Co. 1971. p. 680.
Fisher, Alexander. Is hair dyed with para-phenylene-diamine
allergenic? Contact Dermatitis M4) :226, 1975.
224
-------
Garner, R. C., and C. A. Nutman. Testing of some azo dyes and
their reduction products for mutagenicity using Salmonella
typhimurium TA 1538. Mutat. Res. 44_:9, 1977.
Giles, A. L., and C. W. Chung. Dermal carcinogenicity study by
mouse-skin painting with 2,4-toluenediamine alone or in
representative hair dye formulations. J. Toxicol. Environ.
Health 3^:433, 1976.
Hamblin, D. 0. Aromatic nitro and amino compounds. Ir± Frank A.
Patty (ed.), Industrial Hygiene and Toxicology, vol. II. New
York, Interscience. 1963. p. 2105-2169.
Kachalai, D. P. et al. Effect of m-phenylenediamine on internal
organs and the nervous system. Farmakol. Toksikol. 73; 180-
183, 1973. (Abstract)
Kirk-Othmer Encyclopedia of Chemical Technology, 2nd ed., vol. 15.
New York, John Wiley & Sons. 1968.
MITRE Corp. Scoring of Organic Air Pollutants. 1976.*
NIOSH. Registry of Toxic Effects of Chemical Substances. 1975.
Palmer, K. A., A. Denuzo, and S. Green. The mutagenic assay of some
hair dye components using the thymidine kinase locus of L5
1178Y mouse lymphoma cell. J. Environ. Pathol. Toxicol.
1(1):87, 1977. (Abstract)
Rudner, E. J., W. E. Clendenning et al. Epidemiology of contact
dermatitis in North America: 1972. Arch. Dermatol. 108; 537,
1973.
SRI (Stanford Research Institute). Chemical Economics Handbook.
Menlo Park, Calif. 1975.
SRI. A Study of Industrial Data on Candidate Chemicals for Testing.
August 1977.
Weast, Robert C. (ed.). Handbook of Chemistry and Physics, 52nd ed.
Cleveland, Ohio, Chemical Rubber Co. 1971.
Windholz, Martha. The Merck Index, 9th ed. Rahway, N.J., Merck and
Co. 1976. p. 947-948.
*This document was prepared for the U.S. Environmental Protection
Agency by the MITRE Corp. It is a secondary source and does not
cite its primary references. Thus, verification of some informa-
tion is not possible. The environmental release data were taken
from NSF/Rann Research Program on Hazard Priority Ranking of
Manufacturing Chemicals.
225
-------
CHEMICAL HAZARD INFORMATION PROFILE
Phosgene
Date of report: June 13, 1977
This chemical was chosen for study because it was mentioned
as a possible cause for "Legionnaire's disease." Chlorofluoro-
carbons were reportedly combusted at burning cigarette tips with
phosgene generation leading to the observed respiratory problems.
It is recommended that phosgene be considered for testing.
Very little information is available concerning .the effects of
chronic exposure to phosgene. Knowledge of chronic effects is
important because of phosgene's presence as a common air pol-
lutant. It is also recommended that a Chemical Hazard Informa-
tion Profile be prepared on chloroacyl chlorides since they can
be formed from the same precursors (chlorinated hydrocarbons) as
phosgene.
Note: It was found that phosgene was not the cause of
"Legionnaire's disease."
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may no't reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Chemical Identity
Phosgene, COC12, is a colorless gas at normal temperature
and pressure with a characteristic sweet odor at low concentra-
tions. Phosgene is slightly soluble in water, where it hydro-
lyzes to form HC1 and C02. It is soluble in carbon tetrachloride,
chloroform, benzene, and other organic solvents (NIOSH, 1976).
Phosgene is a heavy gas (3.4 times as heavy as air) and settles
readily in low places (Hardy, 1964).
Production and Use
Most commercially produced phosgene is used captively
because of its great toxicity. Phosgene is manufactured in the
following manner: purified carbon monoxide is mixed with puri-
fied chlorine gas (equimolar or slight excess of CO) and allowed
to react over activated charcoal; the phosgene reaction product
is subsequently purified and condensed (Hardy, 1964). See Table
1 for annual production figures.
226
-------
Table 1. Annual Production of Phosgene (millions of Ib)
1960
1965
1970
1973
37
285
618
728
Less than 2% of all phosgene produced
is used for the merchant market (CEH,
1975).
Phosgene is used most extensively in the production of
toluene diisocyanate (TDI). TDI is a precursor of polyurethane
resins which are used to make foams, elastomers, and coatings. A
rapidly growing use of phosgene is in the manufacture of poly-
methylene polyphenylisocyanate (PMPPI), which is used in the
production of rigid polyurethane foams. Polycarbonate resins are
also based on phosgene and find use as appliance and electrical
tool housings, electronic parts, and break-resistant glazing.
Refer to Table 2 for other uses and an outline of the consumption
pattern (CEH, 1975).
Table 2. Consumption of Phosgene (%)
1965
1969
1970
1973
TDia
PMPPI
Polycarbonate
resins
Otherb
66
5.
2
26.
5
5
62
17
2.
18.
5
5
64.
16
2.
16.
5
6
7
61.
23.
3.
10.
7
6
9
7
This category includes only the 80/20% (by weight)
toluene-2,4-diisocyanate/toluene-2,6-diisocyanate
mixture.
Additional uses for phosgene include the produc-
tion of acyl chlorides, chloroformate esters,
diethyl carbonate, dimethyl carbamyl chloride,
and isocyanates other than TDI and PMPPI; phosgene
is also used in the manufacture of dyes, biocides,
and Pharmaceuticals and as a chlorinating agent
(CEH, 1975).
227
-------
Health Aspects
Human Toxicity
Human exposure to phosgene reported in the literature is
generally limited to episodes of acute overexposure. There are
no pertinent data available concerning the effects of chronic
low-level exposure to phosgene.
Phosgene concentrations of 3 to 5 ppm cause eye and throat
irritation; 25 ppm is dangerous when exposure lasts from 30 to 60
min, and 50 ppm is rapidly fatal after short exposure. Phosgene
poisoning is characterized by a symptom-free latent period of 2
to 24 hr followed by chest pain, shortness of breath, and increas-
ing difficulty in breathing. Severe exposures may lead to rapid
pulmonary edema, which destroys the lung lining and the capacity
for oxygen exchange. Death may occur within 36 hr or less fol-
lowing exposure. In nonfatal cases, no permanent residual damage
is thought to occur (Sax, 1968; Patty, 1963).
Laboratory Animal Toxicity
Acute overexposure to phosgene for short periods of time
generally produces the same symptoms in all animal species tested.
Animals that succumb following exposure display severe pulmonary
edema. Survivors of an acute episode show varying amounts of
bronchopneumonia, benign pneumonia, bronchial plugging, lung
collapse, pulmonary.consolidation, pneumonia, and emphysema
(NIOSH, 1976).
Cameron e.t al. (1942) exposed six mammalian species to 0.2
ppm (0.9 mg/m ) of phosgene for 5 hr daily over 5 consecutive
days. No deaths occurred from the acute exposure, and few
animals displayed any evidence of distress. Necropsy revealed
pulmonary lesions in 67% of the animals, with an estimated 5 to
10% exhibiting moderately severe lesions. Pulmonary edema was
noted in 41%, but was slight in most cases. Repeated exposure at
low concentration was concluded to induce lung damage, though
rarely to a severe degree.
Hygienic Standards
International hygienic standards are as follows: United
States, East Germany, and Czechoslovakia, 0.4 mg/m-' (8-hr TWA for
a 40-hr week); West Germany, 0.5 (8-hr TWA for a 40-hr week);
Sweden, 0.2 (ceiling concentration); U.S.S.R., 0.5 (ceiling
concentration) (Winell, 1975).
220
-------
Environmental Aspects
Atmospheric Formation
The three most readily identifiable sources of phosgene in
air are direct emissions of phosgene during industrial production
or use, thermal decomposition of chlorinated hydrocarbons, and
atmospheric photooxidation of chlorinated hydrocarbons. The
first two sources are likely to represent a significant indoor
hazard, but their contribution to the atmospheric budget is
minimal (Singh, 1976). Photooxidation of chlorinated hydrocar-
bons appears to represent the most probable source of ambient
levels of phosgene.
Singh et al. (1975) reported that simulated tropospheric
irradiation of perchloroethylene in air over a period of 7 days
produced carbon tetrachloride (8% by weight) and phosgene (70 to
80% by weight). Rough calculations based on these figures and
the estimated worldwide emissions of perchloroethylene (450 x 106
kg/year) suggested an annual atmospheric phosgene loading of
between 315 and 382 x 106 kg/year. Gay (1976) reported that 1,1-
dichloroethylene and trichloroethylene as well as perchloroethyl-
ene can be photooxidized (in the lab) to form phosgene and other
reaction products (including the corresponding mono-, di-, and
trichloroacetyl chlorides). Reactivity was in the order of 1,1-
dichloroethylene>trichloroethylene>perchloroethylene. Spence et
al. (1976) experimentally demonstrated the formation of phosgene
following the irradiation of both methylene chloride and chloroform.
Singh (1976) proposes that the photooxidation of chloro-
ethylenes, particularly trichloroethylene and perchloroethylene,
is the primary source of atmospheric phosgene. The cited article
includes the first reported measurements of phosgene in the
ambient air. The phosgene values and those of the chloroethylene
precursors may be found in Table 3. The highest phosgene and
precursor concentrations are found, as expected, at the urban
monitoring locations. Because of the high chloroethylene emis-
sions encountered in urban areas and the relatively reactive
nature of the precursors in the atmosphere, the author feels that
high phosgene concentrations in urban centers could occur during
adverse weather conditions and thereby result in a health hazard.
Laboratory studies also suggest that toxic di- and trichloro-
acetyl chlorides would together be present at about four times
the level of phosgene. The author concludes that the continuous
release of chloroethylenes to the atmosphere in large quantities
may represent a health hazard because of the toxicity of phosgene
and chloroacetyl chlorides, in addition to the toxicity inherent
in chloroethylenes.
229
-------
Table 3. Measured Phosgene and Precursor Levels in Californiac
Nature of site
COC1,
C Cl
CCi
C2HC13
Urban (Los Angeles)
Downwind of urban
Los Angeles
Remote, high altitude
(Badger Pass)
(max.
b
31.7
(8.3)
61.1)
29.3
(6.2)
(max. 44.4)
21.6
(5.1)
(max. 28.8)
673.3
(496.8)
278.1
(232.7)
30.7
(10.5)
310.8
(301.6)
39.7
(83.6)
15.6
(2.5)
Urban- suburban
(Menlo Park)
(max.
30.3
3.2
38.8)
201.9
(413.9)
113.5
(528.5)
Source: Adapted from Singh, 1976.
fAll values are in ppt.
This quantity is the mean of the entire sampling period.
°This quantity is the standard deviation.
Table 4 summarizes the atmospheric chemistry of those chlorinated
hydrocarbons that have been shown to form phosgene in a smog
chamber. Phosgene formation is likely to pose a problem only
during periods of adverse weather such as an inversion. Perchlo-
roethylene and trichloroethylene have the greatest potential for
phosgene formation during such a period due to their short atmos-
pheric half-life.
Table 4. Summary of the Atmospheric Chemistry of Some
Demonstrated Phosgene Precursors
Compound
Chloroform
Methylene
chloride
Estimated
atmospheric
emissions
(106 lb)a
418
Estimated half-
life (years)
0.2
0.3
Tropospheric
chlorinated
reaction
products
Phosgene (67%)
Chlorine monoxide
(33%)
Phosgene (100%)
(HC1?)
230
-------
Table 4. (continued)
Perchloro- 617 0.01 Trichloroacetyl
ethylene chloride (80%)
Phosgene (10%)
Hydrogen chloride
(10%)
Trichloro- 417 0.001 Dichloroacetyl
ethylene chloride (70%)
Phosgene (12%)
Formyl chloride
(8%)
Hydrogen chloride
(10%)
Source:EPA, 1975.'
,1973 domestic emissions.
Quantity in parentheses represents an approximation of the
amount of chlorine from the original compound in each chlo-
rinated reaction product. This column does not account for
all products, only those containing chlorine.
It is difficult to assess the magnitude of the problems of
phosgene formation in the atmosphere. Phosgene is evidently one
of the reaction products of a number of high-volume (both in
terms of production and emissions) chlorinated hydrocarbon
solvents. However, the role and significance of each solvent,
the half-life of phosgene in the air, and the atmospheric fate of
phosgene are not well understood. Nevertheless, it is evident
from Figure 1 that phosgene and the various chloroacetyl chlo-
rides represent the major tropospheric photooxidation products of
chlorinated hydrocarbons.
Cigarettes
Phosgene is known to form following the exposure of certain
chlorinated hydrocarbons to a temperature of 400°C or more. On
the basis of this, several investigators in the 1930's suggested,
without experimental verification, that phosgene could form
either in a smoked cigarette or at its burning tip in the pres-
ence of halogenated hydrocarbons.
Elkins and Levine (1939) carried out the first experiments
which examined the effluent from cigars and cigarettes smoked in
atmospheres containing a number of halogenated hydrocarbon
vapors. Among the organic halides tested were trichloroethylene,
231
-------
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carbon tetrachloride, dichlorobenzene, dichlorofluoromethane,
ethylene dibromide, and ethyl bromide. The analytical method
used did not test the inhaled gases specifically for phosgene,
but measured the total halide content of the combustion gases.
The amount of halide found in the exit gases, however, was so
small that even if all the chloride (or bromide) was present as
phosgene, it would "not constitute a health hazard," or so the
authors concluded.
Little (1955) conducted a series of experiments which
attempted to quantitatively measure the formation of phosgene in
or at the tip of a cigarette. The reported limit of detection
was 0.05 ppm phosgene (v/v). The results of the experiment are
summarized in Table 5. As can be seen, in no instance was phos-
gene detected at or above 0.1 ppm. Even the addition of phosgene
to the experimental atmosphere failed to yield positive results.
Little attributed these findings to the absorption of phosgene by
tar and other constituents of the combusted cigarette. Tar
absorption of phosgene is quite effective, as it was subsequently
found that the tar from a single cigarette could effectively keep
the phosgene in sampled air below the detection limit for 20 min
despite an atmosphere spiked with 50 ppm phosgene and an experi-
mental "smoking" rate of 30 1/hr.
Table 5. Detection of Phosgene in Atmospheres Contaminated
with Chlorinated Hydrocarbons (ppm)
Solvent
Carbon
tetrachloride
Chloroform
Perchloro-
ethylene
Solvent
concen-
tration
50
2,000
300
2,000
200
2,000
Phosgene
in
"inhaled"
gases
<0.1
<0. 1
<0. 1
<0. 1
Phosgene
adjacent
to ciga-
rette tip
<0.1
<0. 1
<0. 1
<0 . 1
<0. 1
<0 . 1
Phosgene
above
cigarette
tip
<0.1
<0.1
<0 . 1
<0. 1
<0. 1
<0 . 1
Tetrachloro- 10
ethane
Trichloro-
ethylene
Phosgene
Phosgene
200 <0. 1 <0. 1 <0. 1
2,000 <0.1 <0.1 <0.1
0.2 <0.1
20 <0.1
Source: Little, 1955.
233
-------
A recent study by Hanst et al. (1977) demonstrated that
chlorofluoromethanes do not decompose to form toxic products
(specifically COC^/ COC1F, and COF2) when in the presence of a
burning cigarette. The experimental procedure called for mix-
tures of chlorofluoromethanes and air to be drawn through ciga-
rettes and then into an infrared absorption cell where the
spectra would be recorded. The yields of COC1F from 2,000 ppm of
trichlorofluoromethane (F-ll) in air and COF2 from 2,500 ppm of
chlorodifluoromethane (F-22) in air were each less than 2 ppm.
No phosgene was detected in either case. In addition, the
spectra showed that the chlorofluoromethanes were not decomposed
in passage through the burning cigarette since the fluorocarbons
were identified in the sample "downstream" from the cigarette.
UV-Induced Formation
A number of solvent degreasers have been shown to react in
air to form phosgene in the presence of short-wave (UV) radiation
generated by welding arcs. Among the chlorinated hydrocarbons
shown to produce phosgene in the described situation are methyl
chloroform (Dahlberg et al. , 1973) ,- trichloroethylene (Dahlberg
and Myrin, 1971; Glass et al., 1971), and perchloroethylene
(Andersson et al., 1975). The consensus among the investigators
was that while all the solvents presented the potential for
phosgene formation, trichloroethylene was the safest because of
the high associated production of dichloroacetyl chloride (5:1
ratio in production of dichloroacetyl chloride to phosgene). The
reasoning was that dichloroacetyl chloride, a strong lachrymatory
agent, would offer adequate warning of the presence of undetect-
able .levels of phosgene. In the case of methyl chloroform, the
production of hydrogen chloride (at about 5 times that of phos-
gene) and trace amounts of acetyl chloride would in combination
be unlikely to produce sufficient irritancy to yield an adequate
warning of the presence of phosgene. Perchloroethylene was seen
as perhaps the most hazardous of the three in this regard because
of its rapid decomposition to phosgene (perchloroethylene absorbs
radiation most strongly at longer wavelengths where the emission
from most welding arcs is very intense). Trichloroacetyl chlo-
ride, which could serve as a phosgene warning agent (because of
its penetrating, lachrymatory smell), was, however, found to have
almost the same rate of production as phosgene and thus would not
give adequate notice (Dahlberg and Myrin, 197L; Dahlberg et al.,
1973; Andersson et al., 1975).
The problem of UV-induced formation of phosgene appears
likely to be of significance only in an occupational context.
234
-------
REFERENCES
Andersson, H. F. et al. Phosgene formation in air contaminated
with perchlorethylene. Ann. Occup. Hyg. 18^(2) :129, 1975.
Cameron, G. R. et al. Effect of exposing different animals to a
low concentration of phosgene 1: 5,000,000 (0.9 mg/m3) for 5
hours on 5 consecutive days. Chapter VIII in First Report on
Phosgene Poisoning, Porton Report No. 2349, Washington, D.C.,
British Defense Staff, British Embassy, April 29, 1942. (As
cited in NIOSH, 1976)
Chemical Economics Handbook (CEH). Menlo Park, Calif., Stanford
Research Institute. 1975.
Dahlberg, J. A., and L. M. Myrin. The formation of dichloroace-
tylchloride and phosgene from trichloroethylene in the atmosphere
of welding shops. Ann. Occup. Hyg. 14_(3):269, 1971.
Dahlberg, J. A. et al. On the formation of phosgene by photo-
oxidation of methyl chloroform in welding. Ann. Occup. Hyg.
16^:41, 1973.
Elkins, H. B., and L. Levine. Decomposition of halogenated
hydrocarbon vapors by smoking. J. Ind. Hyg. 2^:221, 1939.
Gay, Bruce W. Atmospheric oxidation of chlorinated ethylenes.
Environ. Sci. Technol. 10_(1):58, 1976.
Glass, W. I. et al. Phosgene poisoning: Case report. N. Z.
Med. J. 74_(475) :386, 1971.
Hanst, Philip L. et al. Chlorofluoromethanes: Their thermal
stability in passing through cigarettes. U.S. Environmental
Protection Agency, ESRL. January 1977.
Hardy, E. E. Phosgene. In Kirk-Othmer Encyclopedia of Chemical
Technology. 1964.
Little, J. The formation of phosgene by the action of hot sur-
faces and its absence when tobacco is smoked in atmospheres
containing chlorinated hydrocarbon vapours. Br. J. Ind. Med.
.12:304, 1955.
NIOSH. Criteria for a Recommended Standard . . . Occupational
Exposure to Phosgene. U.S. DHEW, PHS, CDC, NIOSH, HEW Publ. No.
(NIOSH)76-137. 1976.
Patty, F. A. Phosgene. In F. A Patty (ed.), Industrial Hygiene
and Toxicology, 2nd ed., vol. 2. New York, John Wiley and Sons.
1963. p. 938-940.
235
-------
Sax, N. Irving (ed.). Dangerous Properties of Industrial Mate-
rials, 3rd ed. New York, Van Nostrand Reinhold Co. 1968.
Singh, H. B. Phosgene in ambient air. Nature 264:428, 1976.
Singh, H. B. et al. Atmospheric formation of carbon tetrachlo-
ride from tetrachloroethylene. Environ. Lett. 1
-------
CHEMICAL HAZARD INFORMATION PROFILE
Sodium Azide
Date of report: August 1, 1977
This chemical was chosen for study because of its proposed
use in automobile air bags.
Sodium azide is not recommended for further priority evalua-
tion within OTS at this time. DOT is studying the safety of its
proposed use in auto air bags.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Sodium azide is a stable, neutral, white to colorless cry-
stalline solid. It decomposes at 300 C and is soluble is water
and liquid ammonia. When sodium azide is dissolved, hydrazoic
acid (HN3) is released from solution (Merck Index, 1969).
Production and Use
Sodium azide is presently used as an intermediate in organic
synthesis (Sutton, 1963) and in the preparation of hydrazoic acid,
lead azide, and pure sodium' (Merck Index, 1969). It also finds
use in fungicidal and nematodicidal compounds, as a preservative
in diluents used with automatic blood cell counters, and as a
common reagent in hospitals and chemical laboratories (Fishbein,
1977). The estimated domestic production in 1974 is less than
1,000 Ib (EPA, 1977).
In June 1977, the Department of Transportation announced that
passive restraints would begin to become mandatory on new auto-
mobiles in 1983. The system that appears most likely to be the
major method of meeting the passive restraint requirements is the
so-called air bag. Briefly, the air bag is a device wherein
impact of the vehicle causes two bags to be instantaneously
237
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inflated to cushion the front seat occupants from the force of
the impact. In the most common air bag designs, the bag is
inflated by means of a solid prochemical composition which, upon
impact, is detonated, forming a gas to inflate the bag. In
these designs, there is a large air bag on the passenger side
of the vehicle that has perforations to allow the bag to deflate
quickly after inflation. A second bag on the driver's side is
much smaller and is not perforated.
Of interest here are the solid pyrochemical compositions.
The primary component of the compositions now most favored for the
air bag is sodium azide (NaNO. This highly toxic substance is
currently produced and used in negligible quantities, but its use
in the air bag would require large production expansion, greatly
increasing the potential environmental and human exposure to it.
(Additional information from the patent literature on the use of
sodium azide for air bag gas generation is given in the appendix.)
According to Department of Transportation estimates, between
11 and 17 million Ib of pyrochemicals will be needed for air bags
annually by about 1990. While the exact proportion of sodium
azide to be used in the pyrochemical composition is unknown, its
production would clearly rise into the millions of pounds per year
to meet the air bag use demand.
The liquid ammonia process is the preferred method for the
production of sodium azide in the United States. In this method,
sodium reacts with liquid ammonia in the presence of a catalyst
(such as ferric nitrate) to form sodamide (NaNH2). The slurry of
sodamide in liquid ammonia produced in this reaction is then
treated with nitrous oxide under pressure to produce the azide.
Sodium azide is separated from the caustic mixture by recrystal-
lization from water (Lemke, 1969).
Health Aspects
Sodium azide is rapidly absorbed from the gastrointestinal
tract and from injection sites; however, the effectiveness of its
absorption from the lungs and skin has apparently been little
studied. Sodium azide is a highly toxic poison for both labora-
tory animals and man. The symptoms generally observed in animals
following acutely lethal dosing are respiratory stimulation and
convulsions followed by nervous system depression and death. With
lower doses the occurrence of convulsions is variable, but there
occurs a consistent, prompt, transient fall in blood pressure.
Rabbits exhibit a 40 to 60% decline in blood pressure following
oral administration of 3 to 10 mg azide per kg. The hypotensive
effect lasts for over 1 hr. At 2 mg/kg, the drop in blood pres-
sure is severe, though of shorter duration. As little as 1 mg/kg
intravenously in cats produces hypotension. Hypertensive patients
characteristically suffer a greater drop in blood pressure than do
normotensive individuals. Doses of 0.01 to 0.02 mg/kg administered
orally to humans produce a prompt fall in blood pressure lasting
10 to 15 min (Sutton, 1963).
238
-------
The following are summaries of the biological effects attributed
to sodium azide.
Mutagenesis
Sodium azide induced a high frequency of mutations with
negligible frequencies of chromosome aberrations in barley seeds
(Milan et al., 1973). In another study, sodium azide treatment of
barley seeds induced a mutation rate of 10 to 30%. No chromosomal
aberrations during the first mitosis were detected in seeds examined
immediately after azide treatment or following 12 months of storage
(Walther, 1975).
Sodium azide is a potent mutagen of salmon sperm DNA in an
acidic environment. The mutagenic activity, however, is not
associated with chromosomal aberrations. The mutagenic effect is
partially explained on the basis of a base substitution mechanism
(Sideris and Argyrakis, 1974).
African violet plants are susceptible to sodium azide-induced
mutagenesis (Warfield, 1974).
Sodium azide effectively reverts S_. typhimurium strain TA1530,
indicating that it is a base substitution mutagen. The chemical
is ineffective on strains TA1531, TA1532, and TA1534, which are
frameshift mutants (Nilan et al., 1973).
Sodium azide treatment has been shown to slightly increase
the frequency of penicillin- and streptomycin-resistant mutants in
Staphylococcus aureus (Berger et al., 1953).
Sodium azide alone failed to induce sex-linked recessive
lethal mutations in Drosophila melanogaster (Sobels, 1954, 1955).
However, when in combination with carbon monoxide, a slight increase
in lethal mutations occurred (Clark, 1958).
Carcinogenesis
A 2-year rat study was conducted to determine the chronic
toxicity or carcinogenicity of sodium azide. Apparently the
maximal tolerated dose (unspecified) and half that level were
given in the diet or by gastric intubation twice weekly to male
and female rats for 18 months followed by a 6-month observation
period. Under the conditions of the experiment, sodium azide was
determined to be noncarcinogenic (Ulland et al., 1973).
Metabolic Effects
Sodium azide interferes with oxidative enzymes and uncouples
oxidative phosphorylation in rat liver mitochondria cells (Zvyagil-
skaya et al., 1969; Bogucka and Wojtczak, 1966). These actions
cause a disruption in energy transfer mechanisms within the cell
and thereby inhibit the production of ATP, the principal energy
storage molecule.
239
-------
Mg-ATPase (an ATP-splitting or energy-releasing enzyme) of
the mitochondrial fraction of rat brain cells was inhibited by
sodium azide (Bigl and Biesold, 1970).
Sodium azide inhibited DNA synthesis and cell division in
S_. typhimurium (Ciesla et al., 1974). It was also found to inhibit
RNA and protein synthesis in ascites ovary carcinoma cells (Stel-
letskaya et al., 1973).
Sodium azide, through disruption of the energy transfer
enzymes, inhibited cilia movement and phagocytosis in Tetrahymena
pyriformis (Burmeister, 1974).
Neurological Effects
Intravenous injections of up to 16 mg of sodium azide per kg
produced a rapid drop in blood pressure, followed by convulsions
accompanied by unconsciousness, vascular congestion, and apnea
(breathing stoppage) in 10 of 11 rhesus monkeys. Cerebellar
damage, ranging from the loss of Purkinje cells of the folia
lining the depth of the horizontal fissures to almost total
decortication (complete removal of the cerebellar lining), was
also produced following the acute exposure. Two of the monkeys
died, and ataxia or loss of muscular coordination developed in
eight of the remaining monkeys. The ataxia, due to cerebellar
cortical"destruction following sodium azide-induced convulsions,
may be attributed to the cumulative effects of impaired ventila-
tion, hypotension, and impaired oxidative enzyme activity (Mettler
and Sax, 1972).
Sodium azide has also been implicated in the production of
dyskinesia, impairment of the power of voluntary movement, in
monkeys (Sassin, 1975).
Daily intramuscular injections of 5 mg sodium azide per kg
into monkeys can, if continued over periods of 4 to 5 weeks,
produce abnormal movements. Necropsies following sacrifice found
basal ganglia necrosis (Hurst, 1942). The same investigator also
found that (daily?) intramuscular doses of 6, 7, and 8 mg/kg
produced symptoms of poisoning on the 17th, 14th, and 8th days,
respectively (Hurst, 1944).
Acute Human Exposure and Hypotension
A male patient in a hematology lab accidentally drank a
solution containing 50 to 60 mg of sodium azide. Within 5 min he
collapsed and briefly lost consciousness. The patient complained
of nausea, a severe headache, and feeling hot. Gastric washing
was performed 10 min following ingestion. After 1 hr, all symptoms
had disappeared except for the headache, which lingered until the
next morning (Richardson et al., 1975).
240
-------
A technician in a hematology lab ingested an estimated 5 to
10 mg of sodium azide. She complained of headache, sweating, and
faintness within 5 min of exposure. The complaints dissipated
shortly thereafter (Richardson et al., 1975)).
In a similar episode, a blood lab technician accidentally
ingested what was estimated to be a "very small amount" of sodium
azide. Symptoms of tachycardia, hyperventilation, and hypotension
were observed. The authors note that the minimal hypotensive dose
in humans lies between 0.2-0.4 g/kg (Roberts et al., 1974).
While acidifying 10 g of sodium azide in a malfunctioning
laboratory hood, a chemist complained of dizziness, weakness,
blurred vision, shortness of breath, and faintness following a few
minutes of exposure. The chemist was observed to have bradycardia
and a moderate reduction in blood pressure. Recovery was complete
in 1 hr (Button, 1963). No estimate of the dose received was
noted in the report; moreover, there was no conclusive demonstra-
tion that the chemist was exposed predominantly to sodium azide,
as it appears likely that hydrazoic acid would also be evolved.
However, the case was seen as important in that it offered the
first demonstration that the effects of respiratory exposure to
simple azides were similar to those seen following oral or IV
administration.
Several additional citations were located which dealt with
acute exposures to sodium azide (Emmett and Ricking, 1975; Kozlicka-
Gojdzinska et al., 1966) . Unfortunately, not enough information
was available in the abstracts to permit a discussion of the
findings.
Environmental Aspects
Phytotoxic Effects
Sodium azide finds some use in fungicidal and nematodicidal
compounds. Because of this use, several investigators have looked
into sodium azide's effects on plants. Within the context of the
present investigation, the phytotoxic characteristics of sodium
azide are of interest with respect to the disposal of the chemical
in conjunction with the junking of an automobile.
The dissipation of sodium azide from soil is significantly
affected by pH, soil moisture, and relative humidity. Acid soils
tend to lose sodium azide more rapidly than do alkaline soils.
The degree of leaching and phytotoxicity is not affected by soil
pH. Bioassay studies indicate that 10 ppm sodium azide in the
soil significantly reduces germination and growth in tested
plants. At levels below 10 ppm, germination is often delayed, but
normal growth occurs following continued dissipation of sodium
azide (Ketchersid and Merkle, 1976).
241
-------
Sodium azide functions as a metabolic poison in plants as in
animals (see "Metabolic Effects"). Sodium azide, however, is not
immediately effective on the cells of plant roots. Nevertheless,
after passage of a lag time to allow penetration and accumulation
of sodium azide in soybean and oat roots (suspended in an aqueous
medium), the respiration capacity of the roots begins to be affected.
The result is a strong increase in the release of soluble organic
substances from the roots. This suggests a direct interaction of
sodium azide with the protein components of cellular membranes
(Shapovalov, 1974).
Stomatal movement in excised leaves is retarded in the presence
of sodium azide. However, stomatal closure is not affected under
the same circumstances. The author proposes that sodium azide
works indirectly on stomata by initially affecting photosynthetic
processes (Permadasa, 1974).
Environmental Chemistry
Sodium azide is stable in water in the absence of light but
appears to be susceptible to photodecomposition by solar radiation.
Photolysis of sodium azide may result in metal nitrides initially,
with the eventual formation of the free metal and nitrogen gas
(EPA, 1977).
APPENDIX. Sodium Azide in Gas Generation
Propellants for automobile air bag inflation are comprised of
fine, solid, inorganic reducing and oxidizing agents in intimate
mixtures. The agents are compacted without binders or solvents
and when combusted produce gases within milliseconds without the
generation of explosive force. Possible reducing agents are salts
of NH2NH2, HN3, or NH20H, while the possible oxidizing agents are
salts of HN03, HN02/ HC104. The combustion products are identi-
fied as N2, 02, and H20, but no CO,or C02- Thus, saturated solu-
tions of NaN3 and NH4C104 are sprayed into a vacuum chamber, the
water is evaporated, and the resulting crystals are collected and
compressed into capsules. When combusted, the product produces a
gas identified as containing (in mole percent) 67% N2, 37% ©2,
1.7% N20, 2.5% H2O, and 0.0% NH3. A pressure of 1.458 psi is
exerted within 0.26 sec (Klager and Dekker, 1974).
A proposed gas-generating agent is composed of a mixture of
alkali metal azide or an alkaline earth metal azide and an equi-
valent amount of NH4C10 or NI^Cl mixed with an oxidizing agent.
Thus, 67 g of NaN3 is mixed (following combination with a styrene-
butadiene copolymer) with 118 g of NH^CK^ to produce the gas-
generating agent. The mixture is divided into four portions and
each is placed in a polyethylene bag (which was previously charged
with lead thiocyanate and KC104). The filled bag is put into a
cylindrical gas generator, then into a 70-liter bag, and ignited.
A pressure of 1.2 kg/cm2 is generated within 31.2 msec and reaches
a maximum of 1.61 kg/cm2, which is maintained for approximately 80
msec (Shiga et al., 1974).
242
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REFERENCES
Berger, H. et al. Effect of sodium azide on radiation damage and
photoreactivation. J. Bacteriol. 6^5:538, 1953.
Bigl, V., and D. Biesold. Isolation of subcellular particle
fractions from brain tissue and distribution of ATP-splitting
enzyme. Acta Biol. Med. Ger. 25_(1) :1, 1970. (Abstract)
Bogucka, K., and L. Wojtczak. Effect of sodium azide on oxidation
and phosphorylation processes in rat-liver mitochondria.
Biochim. Biophys. Acta 122:381, 1966.
Burmeister, J. Action of enzyme poisons on phagocytosis ability,
cilia movement, and metabolism of Tetrahymena pyriformis. Z.
Allg. Mikrobiol. 14.(6) : 479, 1974. (Abstract)
Ciesla, Z., K. Mardarowicz, and T. Klopotowski. Inhibition of DNA
synthesis and cell division in Salmonella typhimurium by
azide. Mol. Gen Genet. .135 (4) :339-348, 1974.
Clark, A. M. Genetic effects of carbon monoxide, cyanide and azide
on Drosophila. Nature 181;500, 1958.
Emmett, E. A., and J. A. Ricking. Fatal self-administration of
sodium azide. Ann. Intern. Med. £3_(2) :224, 1975. (Abstract)
Fishbein, Lawrence. Potential industrial carcinogens and mutagens.
May 1977. (Draft)
Harada, I. et al. Gas-generating agent for inflating protective
bags for passengers in case of automobile accidents. Japan
Kokai 7.4(10) :887, 1972; Chem. Abstr. 8JL:39546E, 1974.
Hurst, E. W. Experimental demyelination of the CNS. I. Poisoning
with potassium cyanide, sodium azide, hydroxylamine, narcotics,
carbon monoxide, etc., with some consideration of the bilateral
necrosis occurring in the basal nuclei. Aust. J. Exp. Biol.
Med. Sci. 2£:297, 1942. (As cited in Mettler, 1974)
Hurst, E. W. Brain 6J:103, 1944. (As cited in Mettler, 1974)
Ketchersid, M. L., and M. G. Merkle. Dissipation and phototoxi-
city of sodium azide in soil. Weed Sci. 2_4_(3):312, 1976.
(Abstract)
Klager, K., and A. 0. Dekker. Non-toxic gas generation. U.S.
Patent 3,814,694, June 4, 1974. Chem. Abstr. 81:172482X,
1974.
Kozlicka-Gojdzinska, H. et al. A case of fatal intoxication with
sodium azide. Arch. Toxikol. 2_2 <3) : 160, 1966.
Lemke, Charles H. Sodium. In Kirk-Othmer Encyclopedia of Chemical
Technology, vol. 18. 1969. p. 432.
243
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The Merck Index, 8th ed. Rahway, N.J., Merck and Co. 1969.
Mettler, F. A. Neuropathological effects of sodium azide adminis-
tration in primates. Fed. Proc. 3,1(5) :1504, 1974.
Mettler, F. A., and D. S. Sax. Cerebellar cortical degeneration
due to acute azide poisoning. Brain 9£(Pt. 3) :505, 1972.
(Abstract)
Nilan, R. A. et al. Azide—A potent mutagen. Mutat.
Res. r?:142, 1973. (Abstract)
Permadasa, M. A. Stomatal movements in excised leaves. Effects
of sodium azide. New Phytol. 73^(4) :689, 1974. (Abstract)
Richardson, S. G. N. et al. Two cases of sodium azide poisoning
by accidental ingestion of Isoton. J. Clin., Pathol. 28:350,
1975.
Roberts, R. J. et al. Accidental exposures to sodium azide. Am.
J. Clin. Pathol. 6J,(6):879, 1974.
Sassin, J. F. Drug induced dyskinesia in monkeys. Adv. Neurol.
1£:47, 1975. (Abstract)
Shapovalov, A. A. Kinetics of the release of water-soluble organic
compounds from the cells of plant roots induced by urea and
sodium azide. Fiziol. Rast. 2,1(6) :1243, 1974. (Abstract)
Shiga, M. et al. Generating gases for inflating protective bags
for passengers in case of automobile accidents. Jpn. Kokai
74^(10) :895, 1974. (Abstract)
Sideris, E. G., and M. Argyrakis. Chemical alterations induced in
DNA and DNA components by the mutagenic agent azide. Biochim.
Biophys. Acta 36^(4):367, 1974. (Abstract)
Sobels, F. H. The effect of pretreatment with cyanide and azide on
the rate of x-ray induced mutations in Drosophila. Z. Verer-
bungsl. £6:399, 1955.
Sobels, F. H. The influence of catalase inhibitors on the rate of
x-ray induced mutations in Drosophila melanogaster. Proc.
1st Int. Photobiol. Congr. Amsterdam. 1954. p. 3~32.
Stelletskaya, N. V. et al. Metabolism of RNA in the presence of
inhibitors of energy metabolism. Biokhimiya 38(6);1267,
1973. (Abstract)
Button, William L. Heterocyclic and miscellaneous nitrogen
compounds. In F. A. Patty (ed.), Industrial Hygiene and
Toxicology, 2nd ed., vol. II. New York, John Wiley and Sons.
1963. p. 2208-2211.
244
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Ulland, B. et al. Chronic toxicity and carcinogenicity of indus-
trial chemicals and pesticides. Toxicol. Appl. Pharmacol.
2_5(3):446, 1973. (Meeting abstract)
U.S. Environmental Protection Agency (EPA). Review of the Environ-
mental Fate of Selected Chemicals. Publ. No. EPA-560/5-77-003.
May 1977.
Walther, F. The influence of storage on sodium azide treated barley
seeds and on the efficiency of the chemomutagen. In; Proceed-
ings of the International Barley Genetics Symposium. 1975.
p. 123-131.
Warfield, D. L. Azide mutagenicity and peroxidase inhibition.
Mutat. Res. 2_3_:399, 1974. (Abstract)
Zvyagilskaya, R. A. et al. Accumulation of azide in mitochondria
and the effect of azide on energy metabolism. Acta Bioshim.
Pol. 16(2), 1969. (Abstract)
245
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CHEMICAL HAZARD INFORMATION PROFILE
Styrene Oxide
Date of report: March 9, 1978
This chemical was chosen for study because it has a relatively
high production volume and because it is a presumed metabolite of
styrene, a very high-volume chemical.
The following recommendations are made regarding further OTE
evaluation of the possible health or environmental hazards of
styrene oxide:
(1) Require TSCA Section 8(a) submission—Little information
is available on the production and uses of styrene
oxide.
(2) Require TSCA Section 8(d) submissions—Information on
chronic toxicity is limited.
(3) Consider need for testing—Styrene oxide is a presumed
metabolite of styrene. If so, there could be extensive
exposure to styrene oxide. Styrene oxide is mutagenic
in several in vitro systems.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Styrene oxide (C6H5CHCH20) is a colorless to pale straw-
colored liquid. It boils at 194.2°C (760 mm Hg) and freezes at
-36.7°C. Synonyms for styrene oxide (CAS No. 96-09-3) include
phenylethylene oxide, phenyl oxirane, 1-phenyl-l,2-epoxyethane,
and 1,2-epoxyethylbenzene. The density of styrene oxide is 1.0540
at 20°C. It is completely soluble in acetone, benzene, carbon
tetrachloride, ethyl ether, heptane, and methanol (Standen, 1965) .
Styrene oxide is miscible with water (0.28% at 25°C). Styrene
oxide is a moderate fire hazard when exposed to heat or flames.
When heated it emits acrid fumes, and it can react with oxidizing
materials (Sax, 1968).
246
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Production and Use
Styrene oxide is made commercially from styrene via the
intermediate chlorohydrin. Styrene oxide could also be prepared
commercially by epoxidation of styrene with peroxyacetic acid. It
is used as a reactive intermediate, especially to produce styrene
glycol and its derivatives. Substantial amounts are also used in
the epoxy resin industry as a diluent (Patty, 1963). It may also
have applications in the preparation of agricultural and bio-
logical chemicals, cosmetics, and surface coatings and in the
treatment of textiles and fibers (IARC, 1976).
Styrene oxide is produced by Union Carbide Corp. in Taft,
La., and Texas City, Tex. (SRI, 1975). It is estimated that 1 to
2 million Ib of styrene oxide is produced annually (SRI, 1977).
Health Aspects
Acute human exposure to styrene oxide causes skin irritation.
Some evidence suggests that styrene oxide is absorbed slowly
through the skin. Styrene oxide is a presumed metabolite of
styrene. Investigations have shown that the ultimate excretion
product in many animals is hippuric acid. Urine of workers exposed
to styrene oxide vapor contained large amounts of mandelic acid
and phenylglyoxylic acid (both compounds in the proposed metabolic
pathway of styrene oxide), but the hippuric acid concentrations
were normal (IARC, 1976).
The LD5Q for oral administration of styrene oxide to rats is
4,290 mg/kg. The LDLg resulting from 4-hr inhalation studies on
rats is 500 ppm, while the LC5Q is 1,000 ppm. The LDsg for styrene
oxide by skin application in male New Zealand rabbits is 1,060
mg/kg. It causes corneal injury in rabbits even at dilutions of
1%. The LD5Q for rats for intraperitoneal injection of styrene
oxide is 460 mg/kg (IARC, 1976; NIOSH, 1976).
No tumors were observed in those mice which survived (33/40)
for 17 to 24 months, during which time they were painted three
times a week with a 5% solution of styrene oxide in acetone. Of a
similar group of 40 mice painted with a 10% solution, only 2
survived to 17 months; neither showed tumors. This study was
designed to screen a large number of epoxides. No information on
a control group or the tumor incidence in a control group was
given (Weil et al., 1963).
Of 30 male mice given thrice-weekly dermal application of 0.1
ml of a 10% solution of styrene oxide in benzene, three developed
skin tumors, and one of these had a squamous cell carcinoma. Of
150 benzene-painted controls, 11 developed skin tumors, and one of
these had a squamous cell carcinoma. The IARC concluded that no
significant increase in skin tumors occurred (IARC, 1976; NIOSH,
1976) .
247
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Styrene oxide induced mutations in strains of Salmonella
typhimurium sensitive to mutagens causing base-pair substitution.
Other styrene metabolites were found nonmutagenic in this study
(Milvy, 1976) . Styrene has also been shown to be mutagenic to
such strains, but only after metabolic activation (Vainio et al.,
1976) . Styrene oxide caused forward mutations in Chinese hamster
cells, as well as in yeast, and was mutagenic in a mitotic gene
conversion system of yeast (Luprieno, 1976).
Environmental Aspects
No information on the environmental aspects of styrene oxide
was found.
REFERENCES
Hawley, Gessner G. (ed.). Condensed Chemical Dictionary,
9th ed. New York, Van Nostrand Reinhold Co. 1977.
IARC (International Agency for Research on Cancer). IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Man,
vol. 11. 1976.
Luprieno, N.A. et al. Mutagenicity of industrial compounds:
Styrene and its possible metabolite styrene oxide. Mutat.
Res. £0(4):317-24, 1976.
Milvy, P. Mutagenic activity of styrene oxide (1,2-epoxyethyl-
benzene), a presumed styrene metabolite. Mutat. Res. 40(1);15-
18, 1976.
NIOSH. Registry of Toxic Effects of Chemical Substances, 1976 ed.
Patty, Frank A. (ed.). Industrial Hygiene and Toxicology, 2nd
ed., vol. II. New York, John Wiley & Sons, Inc. 1963.
p. 1649-1651.
Sax, N. Irving (ed.). Dangerous Properties of Industrial Materials.
New York, Van Nostrand Reinhold Co. 1968.
SRI (Stanford Research Institute). Directory of Chemical Producers.
Menlo Park, Calif. 1975.
SRI. Chemical Economics Handbook. Menlo Park, Calif. 1977.
Standen, Anthony (exec. ed.). Kirk-Othmer Encyclopedia of Chemical
Technology, 2nd ed., vol. 8. New York, John Wiley & Sons,
Inc. 1965. p. 289.
Vainio, H. et al. A study on the mutagenic activity of styrene and
styrene oxide. Scand. J. Work Environ. Health 2(3):147-51,
1976.
Weil, Carrol S. et al. Experimental carcinogenicity and acute
toxicity of representative epoxides. Am. Ind. Hyg. Assoc.
J. 124:305-324, 1963.
248
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CHEMICAL HAZARD INFORMATION PROFILE
Sulfur Hexafluoride
Date of report: July 10, 1978
This chemical was chosen for study because of reports that it
is contaminated with more toxic sulfur compounds, such as S2F10.
The following recommendations are made regarding further OTE
evaluation of the possible health or environmental hazards of
sulfur hexafluoride (SFg):
(1) Defer judgment until additional information is obtained
from a contractor literature search—Current information
is insufficient for judgment.
(2) Request information on composition and purity from
manufacturers—Since SFg itself is a relatively inert
compound, a major concern is the possible presence of
much more toxic impurities.
(3) Update this CHIP based on the additional information
obtained.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Synonyms: Sulfur fluoride, elegas
CAS No.: 551-62-4
Sulfur hexafluoride (SFg) is a colorless, odorless gas. It
has a latent heat of fusion of -50.5°C and a latent heat of subli-
mation of 63.8oc (Braker and Mossman, 1971). SFg is slightly
soluble in water and soluble in alcohol and ether. It is
incombustible (ITII, 1976).
249
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Production and Use
SFg is manufactured by passing fluorine over coarse sulfur,
followed by several purification steps (Braker and Mossman, 1971).
It can be produced by direct fluorination of sulfur or from sulfur
dioxide and fluorine. Major decomposition products of SFg include
hydrogen fluoride (Mazella, 1978), sulfuryl fluoride, and thionyl
fluoride (Sax, 1968).
Two companies are known to be producing SFg, Allied Chemical
and Air Products and Chemicals (Mazella, 1978).
There are no production figures available,, although a spokesman
from Allied Chemicals estimated that production volume centered
around 1 million Ib per year. The spokesman also stated that
Allied Chemical is responsible for the bulk of the production
volume (Mazella, 1978).
SFg is used in various electric power applications as a
gaseous dielectric or insulator. The most extensive use is in
high-voltage transformers. SFg is also used in circuit breakers,
waveguides, linear particle accelerators, Van de Graaff generators,
chemically pumped continuous-wave lasers, transmission lines, and
power distribution substations (Mazella, 1978).
Nonelectrical applications include use as a protective atmos-
phere for casting of magnesium alloys and use as a leak detector
or in tracing moving air masses (Mazella, 1978).
Several sources note that vitreous substitution of SFg in
owl monkeys results in a greater ocular vascular permeability than
that caused by saline. This implies that SFg could have an impor-
tant use in retinal surgery (Constable and Swann, 1975; Fineberg
et al., 1975).
Production and Use of Major Decomposition Products
In 1973, 365,000 short tons of hydrogen fluoride (HF) was
consumed by the United States for a variety of purposes. Major
applications include use in production of fluorocarbons, in pro-
duction of chemicals involved in aluminum smelting and separation
of U-235 and U-238, and as a gasoline alkylation catalyst (CEH,
1976) .
SC-2F2 is used mainly as an insecticide and fumigant. (Vikane ) .
Domestic consumption of S02F2 in this application was 0.9 million
Ib in 1975. S02F2 is also used in organic synthesis and in medicine
and dyestuffs. Production figures for these applications are
lacking (CEH, 1976).
Information on production of 50^2 ^s at a minimum. This
chemical is not listed in the Chemical Week Buyers' Guide Issue,
indicating that it is not produced in marketable quantities. Use
information for this chemical is lacking.
250
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Health Aspects
Sulfur Hexafluoride
SFg is considered to be physiologically inert in the pure
state. It can be absorbed into the body by inhalation, by ingestion,
or through the skin. Only slight effects result, regardless of
the amount absorbed or the extent of exposure. In high concentra-
tions, however, pure SFg can act as a simple asphyxiant by dis-
placing the necessary oxygen (Sax, 1968).
Major Decomposition Products. Ordinarily SFg does not exist in the
pure state. It contains variable quantities of sulfur fluorides. In
the presence of water, these sulfur fluorides can hydrolyze to yield
hydrogen fluoride (HF) and oxyfluoride compounds such as sulfuryl
fluoride (S02F2) and thionyl fluoride (SOF2) (Mazella, 1978). These
compounds have much more toxic health effects.
HF is a toxic, colorless gas with a sharp, penetrating odor.
Vapors and liquid can cause damage to the skin, resulting in
slowly healing sores. The subcutaneous tissues may also be affected,
becoming blanched and bloodless. Gangrene of the affected areas
may result (Sax, 1968).
Inhalation of vapor of HF leads to constricted breathing,
coughing, and irritation of the throat. Ulceration of the upper
respiratory tract or chemical pneumonia may follow (Braker and
Mossman, 1971).
Vapors and liquid HF are very dangerous when in contact with
the eyes (Braker and Mossman, 1971).
S02F2 is a toxic, colorless gas. High concentrations of this
gas may result in narcotic action. Accidental exposure of a human .
worker caused nausea, vomiting, cramps, and itching (Sax, 1968).
Truhaut et al. exposed rats, mice, and rabbits to atmosphere
containing lethal doses of S02F2 for 60-240 min. They found that
S02F2 is a convulsant. Most animals died from asphyxia because
respiratory muscles were blocked by convulsive crisis (Truhaut et
al., 1973).
Truhaut et al. also exposed rats, mice, and rabbits to atmos-
phere containing lethal doses of SOF2 for 60-240 min. They reported
that SOF2 is a pulmonary irritant which induces acute edema. The
exposed animals died of asphyxia (Truhaut et al., 1973).
Environmental Aspects
Sulfur Hexafluoride
SFg is chemically inert in its pure state and does not pose
an immediate threat to the environment (Sax, 1968). SFg has an
atmospheric half-life of 1-3 years (Krey et al., 1976).
251
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Major Decomposition Products. SFg generally occurs in an impure
form, containing variable quantities of sulfur fluorides. Some of
these sulfur fluorides can be highly corrosive. Hydrolysis products
of sulfur fluorides (HF, SOoF,, SOF9) are also highly corrosive (Sax,
1968). ^ Z
REFERENCES
Braker, W., and A. L. Mossman. Matheson Gas Data Book, 5th ed.
East Rutherford, N.J., Matheson Gas Products. 1971. p. 521-
523.
Chemical Economics Handbook (CEH). Menlo Park, Calif., Stanford
Research Institute. July 1976.
Chemical Week Buyers' Guide Issue. 1977.
Constable, I. J., and D. A. Swann. Vitreous substitution with
gases. Arch. Ophthalmol. 93^6) .-416-419, 1975.
Fineberg, E. et al. Sulfur hexafluoride in owl monkey vitreous
cavity. Am. J. Ophthalmol. 7_9_(1) : 67-76, 1975.
International Technical Information Institute (ITII). Toxic and
Hazardous Industrial Chemicals Safety Manual. Tokyo. 1976.
Krey, P. W. et al. Atmospheric residence of sulfur hexafluoride.
U.S. Energy Res. Dev. Admin. April 1976. p. 50-57.
Mazella, Angela (program manager). Production and Use of Sulfur
Hexafluoride. Contract No. EPA-68-01-3899. May 31, 1978.
Sax, I. N. (ed.). Dangerous Properties of Industrial Materials,
3rd ed. New York, Van Nostrand Reinhold Co. 1968. p. 1129.
Truhaut, R. et al. Toxicity of some gaseous fluoride and oxyfluoride
compounds of sulfur. Arch. Mai. Prof. Med. Trav. Secur. Soc.
34(10-11):581-591, 1973.
252
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CHEMICAL HAZARD INFORMATION PROFILE
Tetrahydrofuran
Date of report: October 21, 1977
Revised : November 5, 1979
This chemical was chosen for study because of the high-
exposure potential associated with its use as a solvent.
It is recommended that tetrahydrofuran be considered for
testing. The NTP Chemical Nomination and Selection Committee has
recommended tetrahydrofuran for testing with a medium priority.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
Chemical Identity
Tetrahydrofuran (THF) also known as 1,4-epoxybutane, tetra-
methylene oxide, and diethylene oxide is a colorless liquid with
an ether-like odor and pungent taste (JRB, 1979). THF imports a
characteristic odor to water at or above its olfactory threshold
of 3 mg/1. It boils at 66°C and melts at -108.5°C. THF is a
saturated cyclic ether possessing good solvent properties for
high-molecular-weight polyvinyl chloride, polyvinylidene chlo-
ride, and other organic materials. It is miscible with most
organic solvents as well as with water in all proportions. Mix-
tures of THF and water often exhibit better solvent character-
istics with certain solutes than one or the other alone. THF is
highly flammable and poses a dangerous fire risk. The flash
point of THF is 17°C. THF also forms peroxides readily, and
thus, has explosive potential (Dunlap, 1967; Condensed Chemical
Dictionary, 1977).
Production and Use
THF is currently manufactured in the US by GAF Corporation,
Chemical Products Division and by E.I. Dupont de Nemours and
Company, in La Porte, Texas, where it is produced at approxi-
mately 90 million pounds per year. Quaker Oats Company, Chemical
Division, in Memphis, Tennessee, also manufactures THF at an
estimated annual rate of 15 million pounds (JRB, 1979; SRI,
1978). Imports through principal U.S. customs districts are
reported as (Ibs/yr):
253
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1974 1975 1976 1977
4.2 x 105 8.2 x 104 No data No data
Source:U.S. ITC, 1974-1977.
The furfural-based process used by Quaker Oats Co. involves
the decarboxylation of furfural to furan in the presence of steam
and a zinc-chromium-molybdenum catalyst followed by catalytic
hydrogenation to THF. Approximately eight million pounds of THF
were produced from furfural in 1973.
The second process reacts acetylene and formalydehyde under
high pressure in the presence of a copper catalyst to form
butynediol, which is subsequently hydrogenated to butanediol.
THF is produced via the dehydration of butanediol. The yield of
THF from formaldehyde is about 85% of the theoretical compared to
75% of the theoretical from furfural.
Consumption of formaldehyde-based THF was estimated to have
increased at an annual rate of 30% from 26 million pounds in 1969
to 74 million pounds in 1973. Most of the THF produced from fur-
fural is used captively in the manufacture of polytetramethylene
glycol (.a polyether glycol) which can be used in the production
of spandex fibers, polyurethane elastomers, and elastic poly-
esters. This use represented about 10% of the total estimated
THF consumption in 1973. From 1973 through 1978, the consumption
of formaldehyde-based THF was expected to grow at an annual rate
of 7%, while furfural-based THF consumption was anticipated to
remain essentially static over the period (CEH,, 1974, 1975). See
Table 1 for a summary of domestic consumption figures for THF.
Table 1. Annual Domestic Tetrahydrofuran Consumption
(millions of Ib/year)
Year Consumption
1973 82
1975 90
Source:CEH, 1975; MITRE Corp., 1976.
THF serves as an intermediate in the preparation of numerous
organic chemicals, and is the starting material for the following
compounds (JRB, 1979) : tetramethylene chlorohydrin; 4-chlorobutyl-
benzoate; 1,4-diiodobutane; and 4,4-dichlorodibutyl ether.
THF is used as a solvent for high-molecular polyvinyl
chloride and polyvinylidene chloride during the preparation of
printing inks, adhesives, lacquers, and coating compounds. THF
has been widely used as a solvent in the manufacture of steroids.
254
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A large market for THF is its use as a solvent in the
Grignard reaction-based production of tetraethyl and tetramethyl
lead by the Nalco Chemical Company of Freeport, Texas (CEH,
1975) .
One industry source has estimated that approximately 40% of
THF consumption is in resin and other solvent applications, 20%
as a Grignard reaction solvent, and the remaining 40% as a chem-
ical intermediate (CEH, 1977).
THF is regulated as an indirect food additive. As an
adjuvant and production aid, THF may be used as a solvent in the
coating of film intended for packaging, transporting, or storing
foods, not to exceed 1.5% by weight of film. THF may be used in
the base sheet and coating of cellophane used for packaging food,
not to exceed a residue limit of 0.17% by weight of finished
packaged cellophane. It may also be used as an adjuvant substance
in the preparation of resinous and polymeric coatings for polyolefin
films used as the food contact surface of articles intended for
use in a wide variety of processes involving food (NCI, 1979).
Health Aspects
Human Exposure
NIOSH estimates that 90,000 workers in 3,000 plants are
exposed to THF. The major industries exposed to THF are special
trade contractors and allied products, electric, gas, and sani-
tary services. The major occupations with potential for exposure
to THF are electricians, agriculture and biological technicians,
electric linemen and cablemen (NCI, 1979).
Stoughton and Robbins (1936) reported that operators engaged
in animal studies with THF suffered from severe occipital head-
aches after each experiment (as cited by Browning, 1965).
No toxic effects from industrial exposure to THF are noted
in the literature. On the basis of animal studies, THF is likely
to be somewhat narcotic in man at high concentrations (Browning,
1965).
The adopted TLV-TWA for THF is 200 ppm (590 mg/m3), and the
TLV-STEL (threshold limit value-short term exposure limit) is 250
ppm (700 mg/m3) (ACGIH, 1976).
No epidemiological studies or case reports examining the
relationship between exposure to THF and human cancer incidences
have been found in the literature (NCI, 1979).
Animal-Chronic Effects
Inhalation of THF at a concentration of 200 ppm daily for 6
hours over a period of 3 weeks caused only a fall in the blood
pressure of dogs (Zapp, 1957, as cited by Browning, 1965). Subse-
quent work by Zapp (1971) as cited by ACGIH (1971) showed that
255
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200 ppm THF in daily, 6-hour exposures produced an observable
effect on the pulse pressure of dogs within 3 or 4 weeks. How-
ever, continued exposure to 200 ppm THF for a total of 9 weeks
followed by 3 weeks of exposure to nearly 400 ppm produced no
demonstrable histopathologic changes in the critical organs of
the test population.
Using a much higher dosage of 3,400 ppm daily for 20 days,
Lehmann and Flury (1943) observed severe irritation of the mucous
membranes of rats (as cited by Browning, 1965). One died after
three exposures, and two more cats died after six exposures. In
contrast to Lehmann and Flury, Zapp (1971) found THF to be
neither a skin irritant nor a skin sensitizer. The ACGIH (1971)
placed greater reliance on the conclusions of Zapp because of the
larger test population.
Repeated (oral?) exposure to 40, 100, and 200 rag/kg of THF
for an unspecified amount of time produced "marked cumulative"
changes in white mice. Mice receiving the 100-mg/kg dose devel-
oped moderate weight loss, paralysis of the hind limbs, leukocy-
tosis, decrease and then an increase in oxygen consumption, and
changes in the activity of prothrombin (a blood-clotting factor).
The post mortem revealed marked hyperemia of the viscera and
protein dystrophy of the liver. A 5- to 6-month experiment con-
ducted on mice, rats, and rabbits revealed similar changes fol-
lowing daily (oral?) administration of 20 mg/kg of THF. In
addition, this dose raised the reticulocyte count, reduced cho-
linesterase activity, and lowered the glycogen content in the
liver. A dose of 10 mg/kg, similarly administered, caused mice
to lag in their growth. The long-term administration of 5 mg/kg
of THF was without detrimental effects (Pozdnyakova, 1969).
In a study by Muller and Reichert in 1969, as cited by NCI
(1969) 25 mice received topical applications of 0.1 ml of THF
twice weekly for 25 weeks. After 17.5 months, a total of four
unspecified benign organ tumors were observed. This experiment
may be inadequate for assessment of the carcinogenicity of THF
because of the lack of data on controls and inadequate reporting
of results.
Animal-Acute Effects
The minimum lethal dose of THF for rabbits by oral adminis-
tration is 2.5 g/kg of a 20% solution. The lethal dose in mice
by inhalation is 6.7 volume percent in 30 minutes and 4.9 volume
percent in 51 minutes. A THF concentration of 2.2 volume percent
killed 50% of the exposed mice in 109 minutes. The narcotic dose
of THF by inhalation is, for mice, 6.7 volume percent in 5 min-
utes and 1.1 volume percent in 43 minutes; for dogs, 5.6 volume
percent proves narcotic in 2 hours (Stoughton and Robbins, 1936,
as cited by Browning, 1965).
256
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The LD[-0 (route unknown) of THF was determined to be 2.3
g/kg for mice, 3 g/kg for rats, and 2.3 g/kg for guinea pigs.
Tetrahydrofuran was also somewhat narcotic (Pozdnyakova, 1969).
The acute oral LD50 of tetrahydrofuran in three age groups
of rats was found essentially the same for all age groups (refer
to Table 2 for a summary of results). Tetrahydrofuran was one of
the more toxic of the 16 common solvents tested in this investi-
gation (Kirmura et al., 1971).
Acute oral LD5Q of tetrahydrofuran to three different age
groups of rats resulted in the following values: (a = 95%
confidence limit) 14 days old, 2.3 (1.4-3.8) ; young adult, 3.6
(3.0 - 4.5) ; and older adult, 3.2 (2.6-4.0) (Kimura et al.,
1971) .
Tetrahydrofuran failed to produce evidence of liver damage
following the IP administration of 500 mg/kg to mature guinea
pigs. Of the four tested animals, one died following the single
injection of THF (DiVencenzo and Krasavage, 1974).
The claims of some investigators (Lehmann and Flury in 1943
and Jochmann in 1962, as cited by ACGIH, 1971; Pozdnyakova, 1969)
that oral administration of THF caused kidney, liver, and/or lung
damage in exposed rats have generally not been substantiated by
other workers, although the number of studies is fairly limited
(Browning, 1965; Gleason et al., 1969). It is possible that the
presence of peroxides, a common impurity of tetrahydrofuran, was
responsible in part for these toxic effects not observed by other
investigators (Hoffman and Oettel in 1954, as cited by ACGIH,
1971).
Mutagenicity
No relevant mutagenicity or other in vitro tests on THF were
found in the literature (NCI, 1979).
Environmental Aspects
MITRE Corporation (1976) estimates that approximately 70% of
all THF produced annually in the U.S. is ultimately lost to the
environment during production and predominantly consumption. It
has been detected in a large number of water samples including:
effluent discharge from chemical manufacturing plants (in Indiana,
several cities in Kentucky, and in the Pacolet and Enoree Rivers
in South Carolina), sewage treatment plants (North Carolina),
wood preserving plants (Mississippi) and raw sewage (Schackelford
and Keith, 1976). THF was also detected in air 500 meters from a
factory manufacturing furans and identified as a volatile component
of coffee (NIC, 1979).
THF in the atmosphere is expected to form reactive peroxides
to an unknown degree (MITRE, 1976).
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A Russian investigator, Popov (1971), established that THF
may participate in photochemical atmospheric reactions induced by
UV irradiation (based on laboratory studies). Tetrahydrofuran,
as opposed to other photochemical reactants, yielded few oxidants
following irradiation. Nevertheless/ the cyclic ether's activity
was confirmed by the fairly high conversion rate of nitrogen
oxide to nitrogen dioxide associated with tetrahydrofuran. This
was true despite tetrahydrofuran1s generally low degree of reac-
tivity (compared with other tested organics) as evidenced by the
smooth N02 generation curve identified with THF in Figure 1. The
products of the photochemical reactions between THF and nitrogen
oxide include aldehydes, acrolein/ and formaldehyde. Aldehydes
were produced in somewhat higher quantities. The formation of
acrolein and formaldehyde from THF was observed to occur consid-
erably later in time than was evident in reactions involving more
reactive organic compounds such as heptene (refer to Figure 2).
It will also autooxidize in the presence of light and an
excess of atmospheric oxygen to form resinous products which will
color water variously from pink to brown. This coloring effect,
however, occurs only with relatively high concentrations of THF
(100-250 mg/1) (Pozdnyakova, 1969).
Tetrahydrofuran was detected in distilled water for 1 to 2,
6 to 8, and 10 days, respectively, when the initial concentration
of THF was 0.5, 5, and 10 mg/1. In the presence of microbial
contamination the degradation of THF took 2-3 days less. Thus,
THF may be regarded as a fairly stable compound in water. In
addition, the chemical and biochemical oxidation of THF is
accompanied by considerable consumption of dissolved oxygen
contained in the water (Pozdnyakova, 1969).
Experiments with saprophytic microflora demonstrated that
THF degrades in water to form hydroperoxides among its various
transformation products. One mg of THF produced 1.5 mg of peroxide
compounds, while 2.5 mg of THP produced 3.75 mg of such products.
The formation of hydroperoxides at these concentrations may be
sufficient to exert a bactericidal effect. However, THF at or
below 0.5 mg/1 was biochemically oxidized with very little hydro-
peroxide formation. Thus, the presence of THF in concentrations
exceeding 0.5 mg/1 may disturb the process of natural self-purificatior
occurring in water bodies because of THF's intensive oxygen
consumption and the bactericidal properties of the hydroneroxide
by-product. The Russian author, on the basis of the preceding,
suggested a maximum permissible THF concentration of 5 mg/1 in
water (Pozndyakova, 1969). (The significance of the preceding
article is difficult to assess because of the empirical nature of
the presentation. The author fails to discuss the experimental
method as well as the conditions of each experiment. Thus, such
parameters as temperature, pH, presence of light, the use of open
versus closed flasks, etc., are not noted. Nonetheless, the
concentration of THF required to produce the reported effects is
fairly high (minimum of 170 ppm), especially within the context
of a "natural" situation.)
258
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IRRADIATION TIME, WIN
Figure 1. Dynamics of the conversion of nitrogen
oxide to its dioxide in irradiated mix-
tures of various organic substances with
nitrogen oxide. Legend: 1, THF; 2, hexene-
1; 3, heptene-3; 4, furan; 5, cyclohexane;
6, benzene; 7, furfural. (Source: Popov,
1971.)
4r
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REFERENCES
American Conference of Governmental Industrial Hygienists (ACGIH)
1971. Documentation of the threshold limit values, 3rd ed.
Cincinnati, Ohio:ACGIH.
American Conference of Governmental Industrial Hygienists (ACGIH)
1976. Transactions of the 38th annual meeting of the American
Conference of Governmental Hygienists. Cincinnati, Ohio:ACGIH.
Browning, E. 1965. Toxicity and metabolism of industrial sol-
vents. Amsterdam:Elsevier Publishing Co.
Chemical Economics Handbook (CEH). 1974, 1975, 1977. Menlo Park,
California:Stanford Research Institute.
Condensed Chemical Dictionary, 9th ed. 1977. New York: Van
Nostrand Reinhold Co.
DiVincenzo GD, and Krasavage WJ. 1974. Serum ornithine carbamyl
transferase as a liver response test for exposure to organic
solvents. Am. Ind. Hyg. Assoc. J. 35:21.
Dunlop AP. 1967. Kirk-Othmer Encyclopedia of Chemical Tech-
nology Furfural. New York:Interscience Publishers. Vol 10:249.
Gleason MN, et al. 1969. Clinical toxicology of commercial
products. Baltimore:The Williams and Wilkins Co.
JRB. 1979. Production and use profile:tetrahydrofuran. For the
Office of Toxic Substances, US Environmental Protection Agency.
(Contract No. 68-01-5105).
Kimura, ET et al. 1971. Acute toxicity and limits of solvent
residue for sixteen organic solvents. Toxicol. Appl. Pharmacol.
19:699.
Lehmann, K.B. and F. Flury (1943). Toxicology and Hygiene of
Industrial Solvents, Williams and Wilkins, Baltimore, Maryland.
MITRE Corporation. 1976. Scoring of organic air pollutants:
chemistry, production, and toxicity of selected synthetic organic
chemicals. For US Environmental Protection Agency (Contract No.
68-02-1495).
Muller, E. and J.K. Reichert (1969), Arch. Hyg. Bakt., 153(1),
26-32.
National Cancer Institute (NCI). 1979. Agenda:chemical selec-
tion working group. Conference held at NIH campus. May 24.
260
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Popov VA. 1971. On experimental studies of photochemical
oxidation of organic substances in the atmosphere. Gig. Sanit.
36(2):7.
Pozdnyakova AG. 1969. Hygienic standard for tetrahydrofuran in
water bodies. Gig. Sanit. 34(9):114.
Shackelford WM, and Keith LH. 1976. Frequency of organic compounds
identified in water. Athens, Georgia:Environmental Research
Laboratory, US Environmental Protection Agency.
Slaga TJ et al. 1977. Skin-tumor-initiating ability of benzo(a)
pyrene-7,8-did-9,10-epoxide (anti) when applied topically in
tetrahydrofuran. Cancer Letter. 3(1-2):23-30.
Stanford Research Institute (SRI). 1978. Directory of Chemical
producers USA. Menlo Park, California, p 250.
Stoughton, R.W. and B.H. Robbins (1936) , Anaesthetic Properties
of Tetrahydrofuran, J. Pharm. Exp. Therap., 58:171.
Survey of compounds which have been tested for carcinogenic
activity, 1968-1969 volume. Prepared for the National Cancer
Institute. PHS-149. (DHEW Publ No. (NIH) 72-35).
U.S. International Trade Commission. Imports of Benzenoid
chemicals and products 1974-1977. Washington, B.C. US Govern-
ment Printing Office.
Zapp, J.A., Jr., Personal communication to TLV Committee member,
as cited by ACGIH (1971).
261
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CHEMICAL HAZARD INFORMATION PROFILE
2,4 ,6-Tribromophenol
Date of report: June 2, 1978
This chemical was chosen for study because several TSCA
Section 8(e) submissions have been received on it and because
of dioxin contamination found in analogous chlorine compounds.
The available information is not sufficient for judgment
at this time. Additional information which will be obtained
before making a judgment includes:
(1) Follow-up to 8(e) submitters requesting information
on the composition and purity of tribromophenol
flame retardants, with emphasis on potential
dioxin contamination.
(2) Production volume from the TSCA inventory.
(3) Relevant information held by OPP—Tribromophenol
has reported pesticide uses.
This CHIP will be revised and reevaluated based upon
the additional information obtained.
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Tribromophenol (TBP) is a white crystalline solid which
melts at 95%C. It has a penetrating odor, is insoluble in
water, and is soluble in alcohol, chloroform, ether, and
bases (CCD, 1971; Weast, 1971).
Production and Use
The Directory of Chemical Producers (SRI, 1975) lists
three manufacturers for TBP: Guardian Chemical Corp.,
Michigan Chemical Corp., and White Chemical Corp. No production
volume data were found; however, inclusion in the Directory
262
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implies an annual production level of over 1,000 Ib or value
exceeding $1,000. The Chemical Buyer's Guide (1978) lists six
additional sellers of TBP.
A variety of uses have been reported for TBP. It is used as
an ingredient of Pharmaceuticals and antiseptic germicides and as
a fungicide (Stenger and Atchison, 1967). TBP has been reported
to be an effective snail control agent (Steiner, 1971). Of
greatest interest to OTS is TBP's use as a fire retardant. Great
Lakes recommends TBP as a fire retardant on the following poly-
mers and resins: acrylonitrile-butadiene-styrene (ABS), epoxy,
phenolic, and polystyrene (Brooklyn Polytechnic Institute).
Flammex 3BP reportedly contains TBP and is sold by a British firm
(reference unknown). An analysis of Flammex 3BP showed that the
product contained no dibenzodioxins or dibenzofurans, which are
both highly toxic and are potential contaminants.
Impurities
One of the major concerns is the close structural similarity
to chlorophenol derivatives, which are used as herbicides.
During the production of trichlorophenol, dioxin, a highly toxic
compound, is formed as a contaminant.
Cl ^TCI NaJo^^l
Trichlorophenol Sodium Salt Dioxin
Although one investigator stated that he did not find the
bromine analog of dioxin in a sample of TBP fire retardant,
further research is needed on the production process and possible
contaminants of TBP.
Health Aspects
Toxicity
Little information concerning the toxicrty of tribromophenol
was found in Toxline or Toxback. Howevar, there have been several
Section 8(e) submissions concerning TBF«
The Merck Index (Stecher, 1960) reports that the oral rat
LD5Q is 200 mg/kg; however, Patty (1963) cites an LD5Q of 2,000
mg/kg under similar conditions. TBP is rapidly absorbed from the
gastroenteric tract and in an acute study induced pathological
changes, such as congestion and hemorrhages, in the lungs.
Moderate inflammation of the mucosa, stomach, and intestines was
noted (Patty, 1963) .
Like other halogenated phenols, TBP is capable of both
uncoupling and inhibiting mitochondrial respiration in rat liver
cells (Ratnikova and Yaguzhinskii, 1972; Stockdale and Selwyn,
1971).
263
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The Section 8(e) submissions are summarized briefly
below.
28-Day Subacute Dermal Toxicity Study on Albino Rats'
TBP was slightly irritating to the skin and caused
lesions at the skin test site. Body and organ weights and
blood chemistry were normal. Based on changes in urine pH
and specific gravity, one might suspect that TBP was absorbed
in sufficient quantities to produce kidney damage. However,
the data provided were inadequate to provide for an intelligent
evaluation (8EHQ-1277-0024, 8EHQ-0278-0069).
Pilot Teratology Study in Rats
The pilot study did not contain enough animals per dose
group to be statistically valid. However, rats receiving
1,000 mg/kg/day had slight decreases in body weight between
days 6 and 12 of gestation, an increase in postimplantation
losses, and a slight decrease in the number of viable fetuses
(8EHQ-0378-0095).
Environmental Aspects
Fish Accumulation Study
A 100-fold accumulation of TBP was reported in Carp.
However, test conditions were inadequately described, the
species chosen may have caused an artifically low accumulation
value, and the decomposition products may have higher potential
for accumulation. As stated in the current guidelines for
"substantial risk," a 100-fold bioaccumulation is not considered
a "substantial risk" (8EHQ-0178-0032).
REFERENCES
Brooklyn Polytechnic Institute of New York, Department of Chem-
istry.- Bromine Based Fire Retardants. Unpublished paper.
Condensed Chemical Dictionary (CCD), 8th ed. New York, Van
Nostrand Reinhold Co. 1971.
OPD Chemical Buyer's Guide. New York, Schnell Publishing Co.
1978.
Patty, F. A. (ed.). Industrial Hygiene and Toxicology, vol. II.
New York, Interscience Publishers. 1963. p. 1406.
Ratnikova, L. A., and L. S. Yaguzhinskii. Mechanism of the
inhibition of mitochondrial respiration of the phenol type.
Mitokhondrii 6^:77, 1972. (Abstract)
SRI (Stanford Research Institute). Directory of Chemical Pro-
ducers. Menlo Park, Calif. 1975.
264
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Stecher, P. (ed.). The Merck Index, 7th ed. Rahway, N.J., Merck
& Co., Inc. 1960.
Steiner, A. Snail Control Agents. Swiss Patent No. 510399,
September 15, 1971.
Stenger, V. A., and G. H. Atchison. ^n Kirk-Othmer Encyclopedia
of Chemical Technology, 2nd ed., vol. 3. New York, John Wiley
and Sons. 1967. p. 778.
Stockdale, M., and M. J. Selwyn. Effects of ring substituents on
the activity of phenols as inhibitors and uncouplers of mito-
chondrial respiration. Eur. J. Biochem. ,21(4) :565, 1971. (Abstract)
Weast, R. (ed.). Handbook of Chemistry and Physics, 52nd ed.
Cleveland, Chemical Rubber Co. 1971.
265
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CHEMICAL HAZARD INFORMATION PROFILE
Trichlorobutylene Oxide*
Date of report: January 3, 1978
This chemical was chosen for study because of its
appearance in a technical journal advertisement, thus indicating
some commercial significance, and its structural similarity
to known carcinogens and mutagens. It is recommended that
trichlorobutylene oxide (TCBO) be considered for testing,
chiefly because of its structural similarity to known carcinogens
and mutagens. TSCA Section 8(a) and 8(d) submissions should
be required in order to supplement the very scanty information
currently available.*
This report represents a preliminary investigation of
the subject chemical's potential for injury to human health
and the environment. The information contained in the
report is drawn chiefly from secondary sources and available
reference documents. Because of the limitations of such
sources, it necessarily follows that this report may not
reflect all available information on the subject chemical.
Any recommendations based on this report are tentative
and should not be construed as final Agency policy with
respect to the subject chemical.
Chemical Identity
Trichlorobutylene oxide (TCBO) is a dark amber liquid.
It is miscible with organic solvents such as chloroform,
benzene, and carbon tetrachloride," however, TCBO is insoluble
in water. TCBO has a boiling point of 174°C, but will decom-
pose at 155°C to form HC1 under certain reaction conditions.
Production and Use
It is not known whether TCBO is used commercially at this
time. The only currently available information on the chemical
*Subsequent to the review of this CHIP document and the
selection of the tentative dispositions given above, the
TSCA Interagency Testing Committee recommended halogenated
alkyl epoxides for primary considerations for possible /
testing under Section 4(a) of TSCA (43 F.R. 16684). The EPA
Administrator responded to this recommendations in 44 F.R.
2809528097.
266
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consists of that supplied by Olin Chemicals, the only known
producer. Olin, however, suggests a number of possible applica-
tions:
(1) Urethanes—Chlorinated polyols (homopolymers of TCBO or
copolymers of TCBO with ethylene oxide and/or propylene
oxide) may be prepared. Polyols based on these formula-
tions may increase the tensile strength, surface hard-
ness, and fire retardancy of cast urethanes. Potential
applications include surface coatings, laminated
products, urethane elastomers, adhesives, and foams.
(2) Epoxy resins—TCBO may be cured directly into epoxy
formulations, or the chemical may be prereacted with
amines or alcohols and subsequently be formulated into
epoxy compositions. TCBO addition to epoxy resins is
reported to improve adhesive strength and flame retard-
ancy. Epoxy products containing TCBO may be useful as
adhesives, laminates, coatings, and castings.
(3) Esters—Acrylic esters can be formed by the reaction of
TCBO with acrylic acid; these products may be poly-
merized with other olefins to yield chlorine-containing
polymers. These ester intermediates may find use in
lacquers, lubricants, paints and coatings, adhesives,
and as flame retardants. Polyesters can be prepared
from TCBO and adipic acid, maleic acid, etc., and
possibly find use in laminates, adhesives, and fibers.
(4) Other applications—Suggested uses of TCBO and its
derivatives include: polymerization into phenolic
resins to improve flame retardancy; neutralizing
agents; chemical intermediate; pesticides; polyurethane
and epoxy catalyst; heavy-duty lubricant additive; -
solvents; olefinic polymerization activator; glycols;
plasticizers; modifiers; novel resins; fire-retardant
functional fluids; textiles; vulcanization of graft
polymer rubbers.
Health Aspects
The oral LD5Q of TCBO in rats is 1.5 g/kg. The rabbit acute
dermal LD50 ranges between 0.2 and 2.0 g/kg (abraded?); however,
TCBO is a severe skin irritant in rabbits.
TCBO was found positive in the Ames test.
Environmental Aspects
No information on the environmental fate or effects of TCBO
was found in the sources consulted.
REFERENCES
Olin Chemicals. Application Data: Uses and Chemistry of Tri-
chlorobutylene Oxide (TCBO). Olin Corp. 1977.
Olin Chemicals. Product Data: Trichlorobutylene Oxide, Tech-
nical Grade. Olin Corp. 1977.
267
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CHEMICAL HAZARD INFORMATION PROFILE
1,1,2-Trichloroethane
Date of report: August 1, 1978
This chemical was chosen for study because it was found to be
carcinogenic in an NCI bioassay.
It is recommended that 1,1,2-trichloroethane proceed to
Phase I assessment. It is also recommended that TSCA Section 8(a)
submissions be required for 1,1,2-trichloroethane. The available
production/use information is very sketchy, thus making any exposure
estimate difficult.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
268
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Synonyms: Vinyl trichloride/ ethane trichloride, beta
trichloride
CAS No.: 79-00-5
Chemical Characteristics
The structure of 1,1.2-trichloroethane (1,1,2-TCE), C2H3C13,
is diaarammed below:
Cl Cl
i i
Cl — C — C — H
i i
H H
It is a colorless liquid which boils at 113.S^C and melts at
-36.7°C. 1,1,2-TCE is slightly soluble in water and soluble in
ethanol and ethyl ether (Deichmann et al., 1963).
Production and Use
There is a lack of conclusive evidence available concerning
the production volumes of 1,1,2-TCE. In 1974, Dow Chemical and
PPG Industries were the two producers of 1,1,2-TCE, and production
estimates centered around 124 million lb (NCI, 1978). At present,
Dow Chemical is the sole producer of 1,1,2-TCE, and several
industry contacts have offered a 1978 production figure of 4
million lb (Mazella and Scott, 1978).
Originally, 1,1,2-TCE was used primarily as an intermediate
in vinylidene chloride production; however, this use has been
reportedly terminated by Dow Chemical (Mazella and Scott, 1978).
Additional uses include use in adhesives, in the production of
Teflon tubing, in lacquer, in coating formulations (NCI, 1978),
and as a solvent for fats, waxes, natural resins, alkaloids, and
other products (Mazella and Scott, 1978).
Health Aspects
Harms et al. (1976) observed significant increases in bile
duct-pancreatic fluid and serum glutamate pyruvate transaminase
(SGPT) activity in rats following IP injection of 1,800 mg/kg of
1,1,2-TCE. All rats treated with 1,1,2-TCE also exhibited
centrilobular hepatic necrosis.
26S
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Klaassen and Plaa (1969) observed enhanced hepatic tri-
glyceride levels in male rats only at near-lethal doses. There
was no effect on lipid peroxidation at 0.75 for the LD5 "dose.
The LD by IP injection was 650 mg/kg. The ED5_ for liver
dysfunction, as determined by diminution of phenolsulfonephthalein
excretion, was 570 mg/kg. Necrosis was observed in both liver
and kidneys.
Hanosono et al. (1975) studied the effects of an alloxan-
induced diabetic state on the hepatic response in male rats. At
72 mg/kg IP, 1,1,2-TCE had no significant effect on SGPT activity
or hepatic triglyceride levels in normal rats. In diabetic rats,
however, this dose caused a 17-fold increase in SGPT activity and
a 5-fold increase in hepatic triglycerides.
Watrous and Plaa (1972a, 1972b) determined nephrotoxicity by
taking renal cortical slices from animals treated with 1,1,2-TCE
and measuring the in vitro uptake of organic anions by the tissue.
Significant depression of p-aminohippuric acid uptake occurred in
the tissue of male mice that received 144 mg/kg (SC).
Klaassen and Plaa (1967b) investigated the susceptibility of
male and female mice to the nephrotoxic effects of 1,1,2-TCE.
The ED5Q for renal dysfunction, as determined by PSP excretion,
was 240 mg/kg (IP) in male mice. Renal dysfunction could not be
produced in females, even at lethal doses. The IP LD5Q was 490
mg/kg in males and 580 mg/kg in females.
Kronevi et al. applied 1,1,2-TCE directly on the skin of the
backs of guinea pigs under anesthesia for periods of between 15
min and 12 hr. The epidermis showed morphological changes which
continued to progress as exposure continued. The changes included
pyknotic nuclei, perinuclear edema of basal and suprabasalar
cells, and focal separation of the epidermis from the corium with
vesicle formations. Six hours later, reduction of glycogen
content and hydropic changes in the centrilobular area of liver
tissue were noted, although 12 hr later the changes were less
marked and in nonanesthetized animals they were absent. No
morphological changes were noted in the kidney or the brain.
NCI (1978) conducted a bioassay of 1,1,2-TCE for possible
carcinogenicity of Osborne-Mendel rats and B6C3F1 mice. Control
groups were untreated or gavaged with corn oil, and low- and
high-dose groups were gavaged with 1,1,2-TCE in corn oil. Dose
levels were 42 and 92 mg/kg/day for rats and 195 and 390 mg/kg/day
for mice. No convincing evidence was found for carcinogenicity
270
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of 1,1,2-TCE in Osborne-Mendel rats. The bioassay did provide
evidence that 1,1,2-TCE is carcinogenic in B6C3F1 mice, causing
hepatocellular carcinomas and adrenal pheochromocytomas.
Dermal contact with 1,1,2-TCE is dangerous because it is
readily absorbed through the skin; however, most humans are
exposed to 1,1,2-TCE through inhalation of vapors (NCI, 1978).
OSHA has set forth a time weighted average standard of 10 ppm in
air (NIOSH, 1975) . The threshold limit value for substances in
workroom air is also 10 ppm (ACGIH, 1975) .
Environmental Aspects
The 95-hr LCcn for aquatic life (species unknown) is 10-100
ppm (NIOSH, 1975)7
An EPA monitoring program has detected 1,1,2-TCE in ambient
air in Louisiana, New Jersey, Texas, and California with concen-
trations ranging from 0.000036 mg/m3 to 0.017 mg/nu . The highest
concentration of 1,1,2-TCE was found near a sanitary landfill in
New Jersey (Pellerizi et al. , 1976, 1977).
REFERENCES
ACGIH (American Conference of Governmental Industrial
Hygienists) . Documentation of TLV's. 1971. p. 263.
Deichmann, W. B. et al. In F. A. Patty (ed.), Industrial Hygiene
and Toxicology, vol. 2. New York, John Wiley and Sons, Inc.
1963. p. 1290-1291.
Hanosono, George K. et al. Potentiation of the hepatotoxic
responses to chemicals in alloxan-diabetic rats. Proc. Soc.
Exp. Biol. Med. ^4^:903-907, 1975.
Harms, Molly S. et al. Increased "bile duct-pancreatic fluid"
flow in chlorinated hydrocarbon- treated rats. Toxicol.
Appl. Pharmacol. 35_:4I-49, 1976.
Klaassen, Curtis D. , and Gabriel L. Plaa. Relative effects of
various chlorinated hydrocarbons on liver and kidney function
of dogs. Toxicol. Appl. Pharmacol. IQ_: 119-131, 1967a.
Klaassen, Curtis D. , and Gabriel L. Plaa. Susceptibility of male
and female mice to the nephrotoxic and hepatotoxic properties
of chlorinated hydrocarbons. Proc. Soc. Exp. Biol. Med.
: 1163-1167, 1967b.
Klaassen, Curtis D. , and Gabriel L. Plaa. Comparison of the
biochemical alterations elicited in livers from rats treated
with carbon tetrachloride, chloroform, 1, 1,2-trichloroethane
and 1,1,1-trichloroethane. Biochem. Pharmacol. 18:2019-
2027, 1969.
271
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Kronevi, T., J. Wahlberg, and B. Holmberg. Morphological lesions
in guinea pigs during skin exposure to 1,1,2-trichloroethane.
Acta Pharmacol. Toxicol. £1(4):298-305, 1977.
Mazella, Angela, and Sari Scott. Production and Uses of 1,1,2-
Trichloroethane. Contract No. EPA-68-01-3899. May 5, 1978.
NCI (National Cancer Institute). Bioassay of 1,1,2-Trichloroethane
for Possible Carcinogenicity. DREW Publ. No. (NIH) 78-1324.
January 6, 1978.
NIOSH. Registry of Toxic Effects of Chemical Substances. 1975.
Pellerizi, E. D. et al. Monthly Technical Report Nos. 3, 9, and
12. Contract No. EPA 68-01-1228. 1976.
Pellerizi, E. D. et al. Monthly Technical Report Nos. 2, 8, and
11. Contract No. EPA 68-01-1228. 1977.
Watrous, William M., and Gabriel L. Plaa. Effect of halogenated
hydrocarbons on organic ion accumulation by renal cortical
slices of rats and mice. Toxicol. Appl. Pharmacol. 23;640-
49, 1972a.
Watrous, William M., and Gabriel L. Plaa. The nephrotoxicity of
single and multiple doses of aliphatic chlorinated hydro-
carbon solvents in male mice. Toxicol. Appl. Pharmacol.
23:640-49, 1972b.
272
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CHEMICAL HAZARD INFORMATION PROFILE
Trimellitic Anhydride
Date of report: March 3, 1978
Selection of this chemical for study was prompted by a NIOSH
Current Intelligence Bulletin which reported rather severe respira-
tory problems in workers exposed to trimellitic anhydride (TMA)
vapors. No additional information concerning the effects of TMA
was found in the course of preparing this document.
It is recommended that EPA defer to NIOSH concerning action
on TMA. This recommendation is made in light of the following
considerations:
(1) The use pattern of TMA indicates that exposure is
predominantly confined to the workplace.
(2) Due to its high reactivity, one would not expect
significant environmental levels of TMA.
(3) The health aspects of TMA are well known to NIOSH.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may not reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Chemical Identity
Trimellitic anhydride (1,2,4-benzenetricarboxylic acid, 1,2-
anhydride), CqH4Oc, is a combustible solid which melts at 164-
1660C.
Production and Use
Trimellitic anhydride (TMA) is derived from pseudocumene
(Hawley, 1971). The Directory of Chemical Producers (SRI, 1976)
lists Amoco Chemicals Corp. of Joliet, 111., as the only U.S.
manufacturer of the chemical. SRI estimates that this plant has
a capacity of 50 million Ib per year (EPA, 1977). The Chemical
Week 1978 Buyers Guide Issue lists both Amoco Chemicals Corp. and
Aldrich Chemical Co., Inc., as suppliers of trimellitic anhydride
(McCurdy, 1977).
273
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TMA is used as a curing agent for epoxy and other resins and
in vinyl plasticizers, paints and coatings, polymers, polyesters,
agricultural chemicals, dyes and pigments, Pharmaceuticals,
surface-active agents, modifiers, intermediates/ and specialty
chemicals (NIOSH, 1978) .
The largest market for TMA is as an intermediate in the
production of trimellitate plasticizers. The estimated 1976
production volume of trimellitate plasticizers is 30 million Ib.
These specialty plasticizers are used primarily in polyvinyl
chloride resins where performance over a wide temperature range
is necessary (EPA, 1977) .'
An estimated 7-8 million Ib of TMA was consumed in 1976 for
the production of alkyd (mainly water-based) and oil-free alkyd
(polyester) surface coatings. TMA is also used to manufacture
poly(amide-imide) and poly(ester-imide) resins. An estimated 2.3
million Ib of these resins, which are used as wire enamels, was
produced in 1976 (EPA, 1977) .
Health Aspects
Toxicity
Rice et al. (1977) reported that two workers for a pipe-
coating company developed pulmonary edema following exposure to a
heated epoxy coating material. Exposure occurred during the
spraying of an epoxy powder containing TMA as the curing agent
onto pipes heated to 450°C. One worker developed symptoms after
3 weeks of employment, and the other after 6 weeks. Both workers
showed similar patterns of cough, hemoptysis, and dyspnea. Lung
functions returned toward normal within 1 month of exposure
termination.
Yeiss et al. (1977) investigated illnesses in workers
involved in TMA manufacture. Data on 14 workers suggested three
distinct syndromes induced by TMA inhalation:
(1) Development of rhinitis or asthma after a latent expo-
sure period of weeks to years. Sensitized workers then
exhibited symptoms immediately following exposure.
(2) Onset of cough and dyspnea 4-8 hr after a work shift.
This syndrome also appeared to involve a latent expo-
sure period. Respiratory symptoms were usually accom-
panied by malaise, chills, fever, and muscle and joint
aches ("TMA-flu"). This reaction was associated with
high-dose exposure to TMA.
(3) Irritant effect characterized by rhinorrhea, epistaxis,
cough, dyspnea, and wheezing. No latent period was
associated with this effect.
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Fawcett et al. (1977) also observed the aforementioned
sensitization effect in workers exposed to TMA.
Exposure
A NIOSH Health Hazard Evaluation of a paint and varnish
company which manufactures an epoxy paint found an average air-
borne concentration of 1.5 mg/m^ TMA during processing operations
and 2.8 mg/m3 TMA during decontamination.
In a plant using TMA-epoxy powder pipe coatings, TMA con-
centrations ranged from 11 to 27 mg/m3 (Department of Labour,
Canada).
NIOSH (1978) estimates that approximately 20,000 American
workers are at risk of exposure to TMA. There is no OSHA
standard for TMA. Amoco Chemicals Corp. (1976) suggests a limit
of 0.05 mg/m3.
Environmental Aspects
No information was found concerning the fate and effects of
TMA in the environment. Because of its chemical structure, one
would expect TMA to be rapidly hydrolyzed to trimellitic acid in
aquatic systems.
REFERENCES
Amoco Chemicals Corp., Environmental Health Services, Medical and
Health Services Dept. Amoco — Industrial Hygiene Toxicology and
Safety Data Sheet. July 8, 1976.
Department of Labour, Alberta, Canada. Report to NIOSH. (As
cited in NIOSH, 1978)
Fawcett, I. W., A. J. Taylor, and J. Pepys. Asthma due to
inhaled chemical agents — epoxy resin systems containing phthalic
acid anhydride, trimellitic acid anhydride and triethylene
tetramine. Clin. Allergy 7^(1) : 1-14 , 1977.
Hawley, G. G. (ed.). The Condensed Chemical Dictionary, 8th ed.
New York, Van Nostrand Reinhold Co. 1971.
McCurdy, P. P. (ed.). Chemical Week 1978 Buyers Guide Issue.
New York, McGraw-Hill, Inc. 1977.
NIOSH. Current Intelligence Bulletin 21, Trimellitic Anhydride
(TMA). DHEW (NIOSH) Publ. No. 78-121. 1978.
NIOSH. Health Hazard Evaluation Determination Report No. 74-111-
283. (As cited in NIOSH, 1978)
275
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Rice, D. L., D. E. Jenkins, J. M. Gray, and J. D. Greenberg.
Chemical pneumonitis secondary to inhalation of epoxy pipe
coating. Arch. Environ. Health, July/August 1977, p. 173-178.
SRI (Stanford Research Institute). Directory of Chemical Pro-
ducers. Menlo Park, Calif. 1976.
U.S. Environmental Protection Agency. A Study of Industrial Data
on Candidate Chemicals for Testing. EPA 560/5-77-006, PB 274264.
1977.
Yeiss, C. R., R. Patterson, J. J. Pruzansky, M. M. Miller, M.
Rosenberg, and D. Levitz. Trimellitic anhydride induced airway
syndromes: Clinical and immunologic studies. J. Allergy Clin.
Immunol. 60 (2):96-103, 1977.
276
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CHEMICAL HAZARD INFORMATION PROFILE
Vinyl Bromide
Date of report: January 30, 1978
This chemical was chosen for study because of its structural
similarity to the carcinogen vinyl chloride and its use in special
fire-resistant polymers.
It is recommended that vinyl bromide proceed to Phase I
assessment. Results of a rat inhalation study (8EHQ-0479-0281)
indicate an increased incidence of angiosarcomas at all levels
tested. A study to determine residual vinyl bromide levels in
fabric and fiber samples did not detect vinyl bromide in any
samples at a detection limit of 0.04 ppm.
This information will be forwarded to CPSC on an FYI basis.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may not reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
CHEMICAL HAZARD INFORMATION PROFILE
Vinyl Fluoride
Date of report: January 30, 1978
This chemical was chosen for study because of its structural
similarity to the carcinogen vinyl chloride and its use in special
fire-resistant polymers.
The following recommendations are made regarding further OTE
evaluation of the possible health or environmental hazards of
vinyl fluoride:
(1) Refer to EPA-ORD for mutagenicity testing—No muta-
genicity data are currently available.
(2) Require TSCA Section 8(d) submissions—No information
on chronic studies is readily available.
277
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(3) Check with FDA and NIOSH for additional information—
FDA has apparently evaluated the safety of polyvinyl
fluoride for use in food packaging. NIOSH has sche-
duled a criteria document on vinyl compounds for FY 78.
(4) Update this Chemical Hazard Information Profile based
on the above information.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may not reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
CHEMICAL HAZARD INFORMATION PROFILE
Vinylidene Bromide
Date ofreport:January 30, 1978
This chemical was chosen for study because of its structural
similarity to the suspected carcinogen vinylidene chloride and its
possible use in special fire-resistant polymers.
It is recommended that judgment on this chemical be deferred
until review of the TSCA inventory allows a determination of its
commercial significance. The disposition of this CHIP will be
reconsidered when the inventory has been checked.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily follows
that this report may not reflect all available information on the
subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to the
subject chemical.
278
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CHEMICAL HAZARD INFORMATION PROFILE
Vinylidene Fluoride
Date of report: January 30, 1978
This chemical was chosen for study because of its structural
similarity to the suspected carcinogen vinylidene chloride and its
possible use in special fire-resistant polymers.
It is recommended that TSCA Section 8(d) submissions be
required for this chemical because the available information was
generally sparse. Of particular concern is a total lack of
information on chronic toxicity. This CHIP will be updated based
upon any additional information obtained. If no data are identified,
testing should be considered.
This report represents a preliminary investigation of the
subject chemical's potential for injury to human health and the
environment. The information contained in the report is drawn
chiefly from secondary sources and available reference documents.
Because of the limitations of such sources, it necessarily fol-
lows that this report may not reflect all available information
on the subject chemical.
Any recommendations based on this report are tentative and
should not be construed as final Agency policy with respect to
the subject chemical.
Chemical Identity
Vinyl Bromide
Vinyl bromide (HBrC=CH2) is a colorless gas with a molecular
weight of 106.96. Synonyms for vinyl bromide include bromo-
ethylene and bromoethene. Vinyl bromide melts at -139.54°C and
boils at 15.6°C. Its liquid density at 20°C and saturation
pressure is 1.4933 g/ml. Vinyl bromide is combustible with air
and presents an explosion hazard at moderate concentrations. It
is considered insoluble in water, but soluble in alcohol, acetone,
benzene, and chloroform. Vinyl bromide has relatively low reac-
tivity. This is attributed to resonance involving a polarized
structure:
H\ -H
C-C
X
H
279
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The resonance effect is such that the bond between the bromine
atom and the carbon atom has the characteristics of a double
bond. The bromine atom thus is less labile than it would be if
the bond were purely of a single-bond nature. Vinyl bromide
undergoes polymerization and copolymerization. The bromine atom
is relatively unreactive in nucleophilic substitution reactions.
Vinyl bromide undergoes many reactions typical of olefins (Braker
and Mossman, 1971).
Vinyl Fluoride
Vinyl fluoride (HFC=CH2) is a colorless gas with a mild
odor. The molecular weight of vinyl fluoride is 46.05. Synonyms
for vinyl fluoride include fluoroethylene and fluoroethene.
Vinyl fluoride melts at -160.5°C and boils at -72.2°C. The
liquid density of vinyl fluoride at 10°C and saturation pressure
is 0.6808 g/ml. It is considered insoluble in water and soluble
in ethyl alcohol, acetone, and ethyl ether. Vinyl fluoride is
flammable in air at concentrations between 2.6 and 21.7%. The
net reactivity of vinyl fluoride is decreased by the electron-
attracting effect of the fluorine atom so that it is less reac-
tive toward addition of hydrogen halides than ethylene, even
though the effect is not strong enough to determine the direction
of addition (Braker and Mossman, 1971).
Vinylidene Bromide
Vinylidene bromide (H2C=CBr2) has a molecular weight of
185.85. (It is a liquid with a boiling point of 92°C. Its
specific gravity is 2.1780. This information, which is from the
Preliminary Early Warning Report, has not been confirmed for this
report.)
Vinylidene Fluoride
Vinylidene fluoride (H2C=CF2) is a colorless gas with a
faint ethereal odor. Vinylidene fluoride boils at -83°C and
melts at -144°C. The liquid density at 23.6°C is 0.617 g/ml.
Its molecular weight is 64.04. Vinylidene fluoride presents a
fire risk since it is flammable at concentrations in air between
5.5 and 21.3% by volume. It forms peroxides on exposure to pure
oxygen. Vinylidene fluoride is slightly soluble in water. It is
soluble in ethyl alcohol and very soluble in ether. Synonyms for
vinylidene fluoride include Vinylidene difluoride, Genetron
1132A, 1,1-difluoroethylene, and 1,1-difluoroethene. Vinylidene
fluoride also retains the ethylene characteristic of small
molecular volume and a flat two-dimensional molecular shape
(Burgison et al., 1955; Braker and Mossman, 1971).
280
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Production and Use
Vinyl Bromide
Vinyl bromide can be produced by hydrobromination of
acetylene in the presence of catalysts or by partial debromina-
tion of ethane dibromide with alcoholic potassium hydroxide
(Braker and Mossman, 1971). Commercial manufacturers of vinyl
bromide include Dow Chemical and Ethyl Corp. (Brine Products
Division) (SRI, 1975). It is used as an intermediate in organic
synthesis and for the preparation of plastics by polymerization
and copolymerization. The major use of vinyl bromide is in the
production of flame-retardant synthetic fibers. An example of
this is SEF, a modacrylic fiber produced by Monsanto. The
formula for SEF is 79 to 81% acrylonitrile, 9% vinyl bromide, 8%
vinylidene chloride, and 2 to 4% other. SEF is used primarily in
children's sleepwear. It is produced in a batch polymerization
operation with a suspension polymerization medium and a wet
spinning process (SRI, 1976). This method of production would
probably preclude residual vinyl bromide monomer in the finished
product. Dow Badische Co. estimated (in 1976) its use of vinyl
bromide at 100,000 to 1.5 million Ib annually. They have used it
since 1970.
Vinyl Fluoride
Vinyl fluoride is produced from acetylene and hydrogen
fluoride in the presence of mercury catalysts. Another method is
the addition of hydrogen fluoride to acetylene to form 1,1-
difluoroethane, followed by pyr*olysis to vinyl fluoride (Braker
and Mossman, 1971). Vinyl fluoride is produced by E. I. du Pont
de Nemours and Co., Inc. (SRI, 1975). Since 0.6 Ib of acetylene
is used to produce 1 Ib of vinyl fluoride, and less than 2
million Ib of acetylene is consumed by this industry, the produc-
tion maximum is 3.3 million Ib of vinyl fluoride per year (SRI,
1975). Vinyl fluoride's primary use is as a chemical intermedi-
ate to make polyvinyl fluoride (Teldar) film. Vinyl fluoride has
been in use by E. I. du Pont de Nemours and Co. since 1962.
Polyvinyl fluoride film is characterized by superior resist-
ance to weather, high strength, and a high dielectric constant.
It is used as a film laminate for building materials and in
packaging electrical equipment. Polyvinyl fluoride film poses a
hazard, so it is not recommended for food packaging. Polyvinyl
fluoride evolves toxic fumes upon heating (Hawley, 1977).
Vinylidene Bromide
Vinylidene bromide does not appear to be produced in com-
mercial quantities for any use by any manufacturer.
281
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Vinylidene Fluoride
Vinylidene fluoride can be made by various production pro-
cedures based on pyrolysis. Commercial procedures include pro-
duction of vinylidene fluoride in 43% yield by passing a mixture
of 6 moles of hydrogen and 33 moles of CF^ClCI^Cl over nickel
wire at 490-500°C with a contact time of 10 sec. It has also
been obtained by the dehydrochlorination of CF2C1CH3 (Braker and
Mossman, 1971) and by dechlorination of CH2C1CF2C1 (SRI, 1976).
Vinylidene fluoride is produced by E. I. du Pont de Nemours and
Co. and Scientific Gas Products, Inc. (SRI, 1975). Vinylidene
fluoride is used in the formulation of many polymers and copoly-
mers such as perfluoropropylene-vinylidene fluoride (Viton ,
Fluorel ), chlorotrifluoroethylene-vinylidene fluoride (Kel F ),
polyvinylidene fluoride, and hexafluoropropylene-tetrafluoro-
ethylene-vinylidene fluoride. It is also used as a chemical
intermediate in organic synthesis (Standen, 1966).
Polyvinylidene fluoride is suitable for compression and
injection molding and extrusion. Because of its thermal charac-
teristics (melting point, 340°F), polyvinylidene fluoride (and
polymers containing vinylidene fluoride) can be used in insula-
tion for high-temperature wire and in aircraft missiles. Poly-
vinylidene fluoride is also used in tank linings, chemical tanks,
tubing, and protective paints and coatings (imparting excep-
tional—30 year—resistance to weathering and ultraviolet light),
in impeller parts, shrinkage tubing (to protect resistors and
diodes), and as a soldering joint sealant (Hawley, 1977).
Health Aspects
Vinyl Bromide
Vinyl bromide is considered a moderately toxic substance.
The threshold limit value in air is 250 ppm (NIOSH, 1976),
although a 50-ppm TLV is suggested by other sources (Braker and
Mossman, 1971). The LD5Q for rats is 500 mg/kg (NIOSH, 1976).
In high concentrations, vinyl bromide may produce dizziness,
disorientation, and sleepiness in humans. Vinyl bromide has been
found to be mutagenic to Salmonella typhimurium (strains TA1535
and TA100) using the Ames Salmonella/microsome test (Vincent
Simmons and Dennis Pool, Stanford Research Institute, unpub-
lished) . In another study, vinyl bromide and its presumed
metabolites have been shown to be strong mutagens in Salmonella
typhimurium (Malavell, Bartsch, and Montesono, unpublished;
referred to by Barbin, 1975) .
Vinyl bronide given orally as a 50% solution in corn oil has
an LDjg of about 500 mg/kg in rats. It was not irritating to the
intact or abraded skin of rabbits, but produced slight to moder-
ate eye irritation. In acute inhalation studies, 100,000 ppm
282
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killed rats in 15 min, but if exposure was halted prior to death
the animals recovered completely. Exposure to 50,000 ppm pro-
duced unconsciousness in rats in 25 min. All rats survived 1.5
hr of exposure, but not all survived after 7 hr of exposure.
Those animals that survived 50,000 ppm were sacrificed 2 weeks
after exposure. Slight to moderate damage to the liver and
kidneys was observed after this exposure. Rats exposed to 25,000
ppm vinyl bromide were anesthetized, but all survived for 7 hr at
this level with no abnormalities (Leong and Torkelson, 1970).
In chronic exposure studies, rats inhaling an atmosphere
containing 10,000 ppm vinyl bromide for 7 hr per day, 5 days per
week for 4 weeks became hypoactive and drowsy within 1 hr after
each initiation of exposure, thereafter remaining motionless in
their cages for the duration of the exposure (Leong and Torkel-
son, 1970) .
The rapid onset and recovery of exposed animals from vinyl
bromide's anesthetic effects has led some researchers to suspect
that vinyl bromide is rapidly absorbed by and excreted from the
lungs. On removal, the animals rapidly recovered from drowsiness
and became quite active. The recovery time after treatment
became progressively longer as the experiment progressed. After
15 days of exposure, a decrease in weight gain was observed. The
researchers believed that this was due to decreased feeding
activity. On necropsy of a single moribund rat, which was
sacrificed on the 9th day, gross multifocal gray areas were
observed in the lungs; there were no other gross changes in any
other organs of sacrificed rats. In general the lungs of the
sacrificed rats did not show compound-related changes (Leong and
Torkelson, 1970).
In a more extensive set of studies, rats, rabbits, and
monkeys were exposed to 250 or 500 ppm vinyl bromide for 6 hr per
day, 5 days per week for 6 months. There were no compound-
related effects with respect to demeanor, body and organ weight,
food consumption, a number of hematological parameters, or
mortality. Gross and microscopic examination of the major organs
and tissues revealed no remarkable abnormal changes. All species
experienced minor insignificant decreases in weight gains com-
pared with controls. There was a dose-related increase in non-
volatile blood bromine. All species suffered a somewhat high
rate of miscellaneous lung abnormalities; patchy consolidation
and blanched spots of lung tissue were observed in male rats at
500-ppm level of exposure (this was not statistically signifi-
cant) . No other organs displayed any pathological effects. Male
rabbits showed insignificant increases in the thyroid weight/body
weight ratio at both dosage levels; insignificant increases were
seen in the liver weight/body weight ratio in female monkeys and
spleen weight/body weight ratios in male and female monkeys at
both the 250- and 500-ppm levels. No histological changes were
283
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found in these organs. The heart weight/body weight ratios for
both sexes and the liver weight/body weight ratios for male rats
in 250-ppm exposure group were significantly higher than values
for corresponding control animals (this was not seen at 500 ppm).
On the basis of their work, these researchers recommended that
repeated exposure to vinyl bromide not exceed 500 ppm (with a
time weighted average of 250 ppm) (Leong and Torkelson, 1970).
Vinyl bromide has been tested for activity as a fumigant by
measuring mortality in naked eggs and mature larvae of fruit
flies 48 hr after a 2-hr exposure. The LD50 was found to be
greater than 155 mg/1; therefore, vinyl bromide was judged to be
an ineffective fumigant (Burditt et al., 1963).
In another inhalation study, male rats were exposed to 2%
vinyl bromide 4 or 5 hr per day for 1, 2, 5, or 10 consecutive
days. This treatment was also combined with administration of
sodium phenobarbital (PB) and/or administration of potassium
bromide in the drinking water. Vinyl bromide exposure caused
significant weight loss during the first few days (weight loss
was amplified by administration of PB). The weight loss was
usually due to depression and resulting decreased food intake (as
revealed by pair feeding studies). Behavioral depression may be
attributed to the anesthetic effect of vinyl bromide and the
depressant effect of bromide ion (a known central nervous system
depressant), whose liberation was greatly accelerated by pheno-
barbital. Rats receiving PB along with the vinyl bromide treat-
ment lost more weight than could be accounted for in pair feeding
studies.
The toxicity of vinyl bromide appeared as injury to the
liver, seen during the first 24 to 48 hr of exposure. Repair of
this damage was completed by the 5th day after exposure. Resump-
tion of weight gain corresponded to recovery from liver damage.
Hepatic injury may result from the formation of alkylating agents
from vinyl bromide through the action of liver microsomes. Vinyl
bromide alone did not cause liver aberrations observable by light
microscope. Those animals subjected to PB and vinyl bromide
showed accentuation of hepatic lobular markings. Several grayish
white foci measuring 0.1 to 1 cm were observed in one rat liver
observed after 2 days of exposure. Some rats experienced moder-
ate congestion of the lungs (Van Stee et al., 1977).
Vinyl bromide has been studied in a mouse liver microsome
system. A mixture of vinyl bromide in air [the report contains
conflicting statements of "vinyl bromide/air" and "vinyl bromide
in oxygen (50% by volume)"] was sucked through a medium of liver
microsomes prepared from phenobarbitone-pretreated male mice.
Resultant volatile alkylating metabolites were trapped by reac-
tion with 4-(4-nijtrobenzyl) pyridine (NBP) . The absorption
spectra of the trapped products were identical with those obtained
by reaction of chloroethylene oxide with NBP. The results of
284
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this experiment suggest that vinyl bromide is converted by
microsomal enzymes into the corresponding epoxide, which in this
experiment reacted with NBP. Identification of a metabolic
product of vinyl bromide similar to chloroethylene oxide implies
that vinyl bromide's mutagenic properties may be due to rearrange-
ments similar to those which chloroethylene oxide undergoes
(chloroethylene oxide has the capacity to rearrange to 2-chloro-
acetaldehyde. Both chloroethylene oxide and chloroacetaldehyde
can bind covalently to nucleophilic centers such as adenosine)
(Barbin et al., 1975).
Vinyl Fluoride
Vinyl fluoride is considered nontoxic; however, when it
reaches high concentrations, the oxygen content of the air can
reach a critically low level. The approximate lethal concentra-
tion of vinyl fluoride to most animals has been estimated at
800,000 ppm (Cook and Pierce, 1973). Rats exposed to air con-
taining 20% vinyl fluoride for 30 min showed no noticeable
effects (Braker and Mossman, 1971). At 30% by volume in air,
vinyl fluoride causes slight intoxication. Rats lost their
postural reflex at 60% and lost the righting reflex at 70% vinyl
fluoride in air. Eighty percent vinyl fluoride caused rats to
show slight intoxication and labored breathing (possibly due to
insufficient oxygen). Corneal reflex was retained by rats
exposed to 80% vinyl fluoride for 12.5 hr (Patty, 1963).
Rats were exposed to 3,000 ppm vinyl fluoride for 30 min.
The rats experienced significant mild diuresis. They showed an
increased fluoride ion excretion 4 to 6 days after exposure.
There was no statistically significant increase in creatinine or
sodium ion excretion. Potassium elimination was elevated on the
5th day. These animals showed no significant difference in
growth rates, nor did they show gross pathological changes
except in the kidney (Dilley et al., 1974) (see "Biological
Aspects, Vinylidene Fluoride," for kidney description).
Vinyl fluoride gas was bubbled through a 2% suspension of
rabbit erythrocytes in saline at a rate of 150 ml/min (150
bubbles/min) for 10 min. The reaction vessel was then sealed for
18 hr. The erythrocytes were observed to be crenated after 10
min of exposure, the absorption maxima of the rabbit hemoglobin
were slightly altered, and the electrophoretic characteristics of
the RBC hemoglobin were slightly altered. The cells returned to
their "normal" color within 0.5 min of reexposure to air (Pen-
nington and Fuerst, 1971).
Vinylidene Bromide
Vinylidene bromide has been tested in fed and fasted rats
for short-term inhalation toxicity by measuring survival 24 hr
285
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after a 4-hr exposure period. The vapors were respiratory tract
irritants; they presumably contained HBr gas, a known irritant
which the researchers suspect may have caused the observed injury
and death. The no-effect concentration was set at 46 ppm, since
neither the fed nor the fasted rats died at this exposure level.
At 93 ppm, two of five fasted rats died; none of five fed rats
died. At 471 ppm, three of five fed and five of five fasted rats
were killed. The probable cause of death was acute pulmonary
edema and hemorrhage (Jaeger et al., 1975).
Vinylidene Fluoride
Vinylidene fluoride is considered toxic by inhalation
(Hawley, 1977). The lowest lethal concentration is 128,000 ppm
for a 4-hr exposure (NIOSH, 1976). Vinylidene fluoride has been
reported to be nontoxic to rats at 800,000 ppm (Jaeger et al.,
1975, refer to Lester Greenberg, Acute and chronic toxicity of
some halogenated derivatives of methane and ethane, Arch. Ind.
Hyg. Occup. Med. 2^:335-344, 1950).
Exposure of rats to levels of Vinylidene fluoride ranging
from 40% by volume to 80% (in oxygen) caused the animals to show
an unsteady gait but no loss of reflexes. Exposure was continued
for 19 hr. There were no progressive signs of intoxication.
These animals showed no signs of pulmonary irritation upon sacri-
fice and examination (Patty, 1963) .
Rats were exposed to 2,200 ppm vinylidene fluoride for 30
min. These rats showed a significant increase in urinary excre-
tion of fluoride within 24 hr of exposure and again 4 to 6 days
after exposure. They had a statistically nonsignificant increase
in urine volume. Potassium excretion rose for at least 1 day.
Creatinine and Na+ elimination showed no significant change, and
growth rates were not altered.
Upon sacrifice, no significant pathological changes were
noted except in the kidney. The renal medulla of the kidney
showed marked hyperemia, and there was a pale whitish band in the
cortex near the corticomedullary junction. The midcortical area
sometimes showed ischemic-appearing areas. These changes were
most pronounced on the 3rd and 4th postexposure days and were
almost absent after 2 weeks. Fluoride ion is known to affect
kidney function by interfering with the proximal tubules of the
kidneys. The increase in fluoride excretion tends to support the
hypothesis that many fluoride-containing compounds are biodegrad-
able. The cylic excretion of fluoride suggests that fluorocar-
bons or one of their metabolites are being stored in a compart-
ment with a 5-day turnover rate (Dilley et al., 1974).
A 4-hr exposure of fed and fasted rats to ^27,000 or ^82,000
ppm vinylidene fluoride caused no deaths within 24 hr of expo-
sure. It was not observed to be hepatotoxic (Jaeger et al., 1975)
286
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Another inhalation study on the lethal concentration of
vinylidene fluoride reported that, at the 4-hr exposure level,
128,000 ppm killed two of six or three of six rats (four of six
in a static study). These researchers ranked it as a "slight
hazard" (rank second in a classification system that went from a
low of 1 to a high of 19) (Carpenter et al., 1949). Vinylidene
fluoride retains ethylene's inability to sensitize the heart to
epinephrine (as opposed to chlorination of ethylene, which
produces compounds that cause sensitization and multifocal
ectopic ventricular beats) (Burgison et al., 1955).
Rabbit erythrocytes suspended in saline were exposed to
vinylidene fluoride gas which was bubbled through the medium for
10 min. These cells showed crenation and reduction in size.
They showed no change in electrophoretic characteristics after 10
min of exposure. The erythrocyte suspension was then held in the
sealed reaction vessel for 18 hr. The solution returned to its
original color immediately upon reexposure to air (Pennington and
Fuerst, 1971).
Environmental Aspects
No data on the probable environmental fate and effects of
these compounds have been found in the literature. The low water
solubility of these compounds suggests that aquatic contamination
is improbable. Their release into the atmosphere seems unlikely
except in the case of a rare accidental spill or unless one of
the polymers contains an abnormally large amount of the unreacted
monomer. Hence, the potential environmental threat posed by
these materials is probably low.
APPENDIX. Pyrolysis of Polymers Containing
Vinylidene Fluoride
Pyrolysis products of polymers containing vinylidene fluo-
ride and hexafluoropropene were found to be less toxic than those
of polytetrafluoroethylene (Teflon ) (Carter et al., 1974).
Three compounds were considered: a copolymer of vinylidene
fluoride and hexafluoropropene (VF2/HFP); a copolymer of vinyli-
dene fluoride and hexafluoropropene with "additives to provide
improved properties," (VF2/HFP-A); and a tetrafluoroethylene
(VF^/HFP/TFE). The studies were conducted on groups of 10 male
(225 to 250 g) Sprague-Dawley rats in a 142-liter chamber, with a
30-min exposure period. These polymers were found to be similar
in their thermal degradation characteristics.
Complete thermal degradation of these polymers occurs at
525-550°C. The LD50 for F2/HFP is 2.36 g of the polymer pyro-
lyzed in the chamber at 550°C. The LDsg for VF2/HFP/TFE is 1.52
g; VF2/HFP-A has an LDso of 1.06 g. For 800°C pyrolysis, the
LD50's are as follows: 0.59 g for VF2/HFP; 0.42 g for VF2/HFP/TFE;
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0.46 g for VF2/HFP-A. The VF2/HFP pyrolysate appears to be the
least toxic. Death due to exposure generally occurred within 48
hr. Most animals died from 4 to 24 hr postexposure, but no
animals died during exposure. Gross and histological examination
of tissues from the rats exposed to lethal levels of the pyroly-
sates revealed lesions characteristic of the response following
exposure to severe pulmonary irritants. This response was
characterized by initial capillary damage leading to pulmonary
edema, with accompanying alveolar cell hypertrophy and desquama-
tion. If the animal survived, the lungs returned to normal
within 1 week of exposure. No other organ system was found to
have been affected by the exposure, including the renal system.
The exact composition of the pyrolysate fumes was not stated.
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA 560/11-80-011
2.
3. RECIPIENT'S ACCESSION-NO.
4. TITLE AND SUBTITLE
Chemical Hazard Information Profiles (CHIPs)
August 1, 1976, to November 20, 1979
5. REPORT DATE
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Chemical Hazard Identification Branch/Assessment
Division/OTE/OPTS/EPA
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Pesticides and Toxic Substances TS-792
U.S. Environmental Protection Agency
401 M. Street, S.W.
Washington. D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
8-1-76 to 11-20-79
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This collection of 40 Chemical Hazard Information Profile (CHIP) re-
ports was prepared by the Office of Pesticides and Toxic Substances
(OPTS) between August 1, 1976, and November 20, 1979. Chemicals are
chosen for CHIP preparation on the basis of information indicating
potential for adverse health or environmental effects of significant
exposure. The CHIP itself is a brief summary of readily available
information concerning health and environmental effects and exposure
potential of a chemical. Information gathering for a CHIP is gener-
ally limited to a search of secondary literature sources and is not
intended to be exhaustive; however, in depth searches on specific
topics may be done on a case-by-case basis. In general, no attempt is
made to evaluate or validate information at this stage of assessment.
Preparation of a CHIP is part of the first stage in the OPTS Chemical
Risk Assessment Process. The purpose of the CHIP is to enable OPTS to
make a tentative decision on an appropriate course of action for the
subject chemical and to identify and characterize problems that may
require more thorough investigation and evaluation.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
18. DISTRIBUTION STATEMENT
19. SECURITY CLASS (This Report)
21. NO. OF PAGE
20. SECURITY CLASS (This page)
22. PRICE
EPA Form Z220-1 (9-73)
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