EPA/600/8-89/072
July 1990
Summary Review of Health Effects
Associated with Elemental and
Inorganic Phosphorus Compounds:
Health Issue Assessment
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
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Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or
recommendation for use.
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Preface
The Office of Health and Environmental Assessment has prepared this
health assessment to serve as a source document for EPA use. The summary
health assessment was developed for use by the Office of Air Quality Planning
and Standards to support decision making regarding possible regulation of
phosphorus as a hazardous air pollutants.
In the development of the assessment document, the scientific literature
has been inventoried through January 1989, key studies have been evaluated,
and summary/conclusions have been prepared so that the chemicals' toxicity
and related characteristics are qualitatively identified. Observed effect levels
and other measures of dose-response, relationships are discussed, where
appropriate, so that the nature of the adverse health responses is placed in
perspective with observed environmental levels.
Any information regarding sources, emissions,'ambient air concentrations,
and public exposure has been included only to give the reader a preliminary
indication of the potential presence of this substance in the ambient air. While
the available information is presented as accurately as possible, it is
acknowledged to be limited and dependent in many instances on assumption
rather than specific data. This information is not intended, nor should it be
used, to support any conclusions regarding risk to public health.
If a review of the health information indicates that the Agency should
consider regulatory action for this substance, considerable effort will be
undertaken to obtain appropriate information regarding sources, emissions,
and ambient air concentrations. Such data will provide additional information
for drawing regulatory conclusions regarding the extent and significance of
public exposure to this substance.
in
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ABSTRACT
' Phosphorus is a nonmetallic essential element. Although phosphorus
occurs naturally in the environment, most of the phosphorus in the
environment occurs during its manufacture into one of the three allotropic
forms (white, red, or black) or into phosphorus compounds and during the
transport and use of these compounds.
White phosphorus/felt and red phosphorus/butyl rubber are irritating to the
skin and eyes. Phosphoric acid, phosphorus pentoxide, and the phosphorus
chlorides are irritating, in some cases corrosive, to the skin, eyes, and mucous
membranes. Inhalation of these compounds has produced respiratory tract
irritation in mammals. The phosphorus chlorides have also produced effects
on the kidney, liver, and nervous system of experimental animals. Phosphine
is highly toxic by the inhalation route of exposure and has reportedly produced
gastrointestinal, cardiorespiratory, and central nervous system effects in
humans. A definite conclusion regarding the possible reproductive/
teratogenic, mutagenic, or carcinogenic potential of these compounds cannot
be drawn because of the lack of adequate studies.
IV
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Table of Contents
Preface iii
Abstract iv
Tables ; vii
Authors and Reviewers viii
1. Summary and Conclusions 1
1.1 Elemental Phosphorus . 1
1.2 Inorganic Phosphorus Compounds 6
2. Background Information 15
2.1 Chemical Characterization ancr Measurement 15
2.1.1 Elemental Phosphorus 15
2.1.2 Inorganic Phosphorus Compounds 16
2.2 Production and Uses 16
2.2.1 Elemental Phosphorus 16
2.2.2 Inorganic Phosphorus Compounds 17
2.3 Environmental Release and Exposure 19
2.3.1 Elemental Phosphorus 19
2.3.2 Inorganic Phosphorus Compounds 21
2.4 Environmental Fate 22
2.4.1 Elemental Phosphorus 22
2.4.2 Inorganic Phosphorus Compounds 22
2.5 Environmental Effects 22
2.5.1 Elemental Phosphorus . 22
2.5.2 Inorganic Phosphorus Compounds 24
3. Health Effects 27
3.1 Pharmacokinetics and Metabolism 27
3.1.1 Elemental Phosphorus 27
3.1.2 Inorganic Phosphorus Compounds 29
3.2 Biochemical Effects 30
3.2.1 Elemental Phosphorus 30
3.2.2 Inorganic Phosphorus Compounds . 31
3.3 Acute Toxicity 31
3.3.1 Elemental Phosphorus 31
3.3.2 Inorganic Phosphorus Compounds 34
3.4 Subchronic and Chronic Toxicity 36
3.4.1 Elemental Phosphorus 36
3.4.2 Inorganic Phosphorus Compounds 41
3.5 Teratogenicity and Reproductive Effects 42
3.5.1 Elemental Phosphorus 42
3.5.2 Inorganic Phosphorus Compounds 42
3.6 Mutagenicity 42
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3.6.1 Elemental Phosphorus 42
3.6.2 Inorganic Phosphorus Compounds 44
3.7 Carcinogenicity 44
3.7.1 Elemental Phosphorus 44
3.7.2 Inorganic Phosphorus Compounds 44
3.8 Effects on Humans 45
3.8.1 Elemental Phosphorus 45
3.8.2 Inorganic Phosphorus Compounds 50
4. References
57
VI
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List of Tables
No.
1-T Summary of Significant Toxic Effects of Elemental
Phosphorus Compounds 2
1 -2 Summary of Significant Toxic Effects of Inorganic
Phosphorus Compounds 7
2-1 United States Producers of Elemental Phosphorus (1988) . 17
2-2 Estimated Emission Factors for Point Source Emission of
Phosphorus to the Environment . . . 20
3-1 Distribution and Excretion of Radioactivity in Rats Receiving
32P White Phosphorus 29
3-2 Lethality of Phosphine in Animals 35
3-3 Oral and Subcutaneous Toxicity of White Phosphorus in Rats 40
3-4 White Phosphorus/felt Smoke Induced Visceral and Skeletal
Variations and Abnormalities 43
3-5 Gross Symptoms of Patients who Ingested Elemental
Phosphorus .. 47
3-6 Oral Toxicity of Elemental Phosphorus in Humans 48
3-7 Acute Hazard Levels of Phosphine in Humans 52
VII
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AUTHORS AND REVIEWERS
This document was prepared by the Oak Ridge National Laboratory under
contract with the Environmental Criteria and Assessment Office, EPA
Research Triangle Park, N.C. (Beverly Comfort, Project Manager).
Drafts of this document have been reviewed for scientific and technical
merit by Lena Brattsten, Senior Research Biologist and Associate Professor,
E. I. du Pont de Nemours and Company, Inc., Wilmington, Delaware and
Eugene J. Olajos, Chemical Research Development and Research Command,
Aberdeen, Proving Ground, Maryland. In addition, it has been reviewed by
members of the Human Health Assessment Group (HHAG), and the Exposure
Assessment Group (EAG) of the Office of Health and Environmental
Assessment (OHEA), EPA, Washington, D.C.
VIII
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1. Summary and Conclusions
1.1 ELEMENTAL PHOSPHORUS
Phosphorus, a nonmetallic essential element, occurs in three allotropic
modifications: white (or yellow), red, and black. White phosphorus, the best
known form, is a highly reactive tetrahedral molecule that occurs almost
exclusively as salts of phosphoric acid. Red phosphorus is less reactive and is
produced by heating white phosphorus in an inert atmosphere. Black
phosphorus is produced from white phosphorus under pressure.
Phosphorus can be released into the atmosphere during its manufacture,
transport, or conversion to products such as detergents, phosphoric acid,
munitions, fireworks, insecticides, and rat poison. Volatilization from soil and
water and remobilization from sinks (i.e., soil and aquatic sediments) may also
occur.
The only study found in the published literature on the levels of elemental
phosphorus in air reported levels of up to 2.46 mg/m3 in the form of particulate
matter in the vicinity of St. Louis, Missouri. However, estimates have been
made of the amount of phosphorus released in the air as a result of mining
and the manufacture, use, and disposal of phosphorus containing products.
According to the U. S. Environmental Protection Agency, the largest
single source of phosphorus air emissions is the combustion of coal,
accounting for 23 percent of the total ambient air concentration of phosphorus.
Estimates of white phosphorus releases from white phosphorus/felt munitions
manufacture place the emission of elemental phosphorus at 0.5 mg/m3 as a
worst-case upper limit and a 1 -hour exposure of 0.5 g/m3 in resting humans,
but exposure to concentrations as low as 185 mg/m3 for 5 minutes may
produce sore throat, coughing, nasal discharge, tightness in the chest, and
congestion. In one study, inhalation of an unknown amount of white
phosphorus for 15 to 20 minutes also caused laryngitis, which persisted for
several months. Toxic symptoms observed in some workers accidentally
exposed to 35 mg/m3 of phosphorus and 22 mg/mS of phosphorus pentoxide
for 2 to 6 hours at 7-hour intervals (total exposure time not given) included
weakness, malaise, headache, vertigo, tracheobronchitis, and tenderness and
enlargement of the liver.
Elemental white phosphorus can be absorbed by ingestion, inhalation, and
dermal contact. The major tissues accumulating white phosphorus and liver,
kidney, lung, bone, and skeletal muscle. One inhalation study with
radiolabelled red phosphorus in mice showed the chemical to be distributed in
the digestive and respiratory tracts. After two days, only the lungs showed
some radioactivity which was retained there for at least 10 days. White
phosphorus is eliminated from the body through urine and feces.
Available studies on health effects of elemental phosporus deal primarily
with white phosphorus, and to a lesser extent with red phosphorus.
Additionally, much of the research examines the effects of exposure to
phosphorus smoke compounds, specifically white phosphorus/felt and red
phosphorus/butyl rubber and their combustion products. Table 1-1
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summarizes significant toxic effects of elemental phospoms compounds,
emphasizing those effects produced by inhalation and indicating significant
data gaps.
The effects of acute exposure by inhalation to white and red phosphorus
and smoke compounds are similar in laboratory animals and humans and are
usually limited to the upper respiratory tract. Overt effects are nasal discharge,
coughing, sore throat, difficult breathing, laryngitis, and bronchitis. Sensitivity
to white phosphorus/felt or red phosphorus/butyl rubber smoke via inhalation
appears to be greatest in guinea pigs. Acute phosphorus intoxication in
humans from inhalation has not often been reported. However, the estimated
minimum harassing exposure concentration is 700 mg/m3 in working humans
and 1,000 ng/'m3 in resting humans, but exposure to concentrations as low as
185 mg/m3 for 5 minutes may produce sore throat, coughing, nasal discharge,
tightness in the chest, and congestion. In one study, inhalation of an unknown
amount of white phosphorus for 15 to 20 minutes also caused laryngitis, which
persisted for several months. Toxic symptoms observed in some workers
accidentally exposed to 35 mg/m3 of phosphorus and 22 mg/m3 of
phosphorus pentoxide for 2 to 6 hours at 7-hour intervals (total exposure time
not given) included weakness, malaise, headache, vertigo, tracheobronchitis,
and tenderness and enlargement of the liver.
The' minimum lethal oral dose of white phosphorus in humans is
estimated to be 100 mg (1.4 mg/kg), but could be as low as 50 mg (0.7 mg/kg)
for a 70-kg individual. An oral dose of 15 mg (0.2 mg/kg) may cause toxic
effects. After acute oral intake, the major target organs damaged by white
phosphorus in laboratory animals and humans are the gastrointestinal tract,
liver, kidney, brain, and cardiovascular system. The effects on the
gastrointestinal tract are due to local irritation, whereas the effects on the other
organs are due to systemic absorption. A characteristic lesion due to white
phosphorus intoxication is fatty degeneration of the liver in both laboratory
animals and humans.
Unlike acute exposure, which causes similar effects in laboratory animals
and humans, different effects have been observed in animals and humans
following subchronic/chronic exposure to white phosphorus. In laboratory
animals, oral or subcutaneous administration causes reduced growth, reduced
survival at high doses, and increased survival at low doses. Liver damage is
usually moderate. Characteristic bone pathology, observed at doses as low as
0.05 mg/kg/day in rats and guinea pigs, involves a thickening of the
epiphyseal line and extension of trabeculae into the shaft. Rats exposed via
inhalation to a vapor concentration of 150 to 160 mg/m3 of yellow phosphorus
30 minutes daily for 60 days also develop the typically widened epiphyseai
line, pronounced trabeculation with insufficient ossification, and abnormal
development of long bones. These abnormalities are different from the
necrosis of the jaw produced in humans by chronic occupational exposure to
white phosphorus.
Subchronic inhalation exposure of laboratory animals to white
phosphorus/ felt smoke causes lesions in the respiratory tract similar to those
in humans after acute inhalation exposure. The mortality rate in rats exposed
to 1,161 mg/m3 15 minutes/day for 13 weeks was 40 percent.
Histopathological examination revealed laryngitis, tracheitis, congestion, and
bronchitis. A lowest-observed-adverse-effect-level (LOAEL), based on effects
on the respiratory tract, changes in body and organ weights, and blood
chemistry and hematology, was 193 mg/m3.
Phosphorus toxicity was mostly seen in factory workers in the early
1900's who were exposed to phosphorus vapor for a considerable length of
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time. Humans occupationally exposed to white phosphorus may develop
necrosis of the jawbone, a specific suppurative lesion that can result in the
loss of some or all of the upper or lower jawbone. Necrosis of the jawbone
may appear as early as 3 months or as late as 23 years after initial exposure.
The airborne levels of phosphorus were not known in the case histories of
phosphorus necrosis presented in the literature; therefore the disease process
cannot be correlated with concentrations of phosphorus in air.
A study of healthy workers in a phosphorus plant, with exposure times
ranging from 1 to 17 years, revealed no statistical differences in hematology
and plasma levels of inorganic phosphorus, alkaline phosphatase, calcium, or
magnesium; nor were there differences in bone density. In contrast, a recent
Russian study reported liver damage and possible bone abnormalities in
industrial workers engaged in the production of yellow phosphorus. Exposure
reportedly ranged from 3 to 5 years at the maximal permissible air concentra-
tion and occasional elevated levels of phosphorus. The maximum allowable
level established in the Soviet Union is 0.03 mg/m3.
White phosphorus/felt smoke at a concentration of 1,000 mg/m3 induced a
few major malformations consisting of brachygnathia, thin-walled heart, and
reversed ductus arteriosus in rats. These malformations have not been
confirmed; however, exposure to white phosphorus/felt smoke does cause
reduce survival, viability, and lactation indices in pups at 1,000 mg/m3.
In one report, female rats administered 0.75 mg/kg of yellow phosphorus
orally for 80 days prior to relating, and through two gestation periods, experi-
enced a high mortality rate. A total of 13 females (43 percent) died within two
days of parturition and the deaths were attributed to difficulty in parturition.
Doses of 0.015 and 0.005 mg/kg had no adverse effects. A no-observed-
adverse-effect level (NOAEL) of 0.015 mg/kg was established.
There is no evidence that elemental phosphorus induces teratogenic or
reproductive effects in humans. There were also no available studies regarding
carcinogenicity and therefore, elemental phosphorus is classified in Group D
according to the U. S. Environmental Protection Agency guidelines on
carcinogenicity.
1.2 Inorganic Phosphorus Compounds
Only limited information was found in the published literature on the
effects of the selected inorganic phosphorus compounds in humans and
experimental animals. A.summary of the reported effects appears in Table 1-2.
Phosphine (PH3), a toxic gas with an unpleasant odor of decaying fish,
may be emitted from processes such as metal shaving, sulfuric acid tank
cleaning, generation of acetylene from impure calcium carbide, and the
handling of phosphorus explosives. Phosphine evolves when acid or water
come in contact with metallic" phosphides. It is used for fumigation of grain
and is generated by reacting aluminum or calcium phosphide with water. It is
released in small quantities from combustion of white and red phosphorus
screening smokes. An estimated half-life of 2 to 8 hours in the atmosphere
indicates that it would not persist in the environment.
The 4-hour LC50 of 15*4 mg/m3 in rats indicates that phosphine is highly
toxic by the inhalation route of exposure. Little species variation has been
observed in laboratory animals exposed to this chemical. The effects of acute
exposure preceding death are mainly secondary to respiratory tract damages.
Pathological changes in animals exposed to high concentrations of phosphine
(about 560 mg/m3) include pulmonary edema, liver and kidney effects, and
degenerative changes in the brain. Low concentrations (3.75 mg/m3) have
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been tolerated for 34 days without clinical injury. Long-term ingestion of a
phosphme-fumigated diet containing 0.99 mg/kg reportedly produced no
adverse effects in rats.
Poisoning via inhalation in humans, usually an accidental occurrence, has
resulted from grain fumigation, releases from ferrous alloys stored on ships,
the generation of acetylene from portable generators used by welders, and
exposure in submarines carrying sodium phosphide warning lights. Phosphine
is readily absorbed by the lungs and gastrointestinal tract; some of the
absorbed phosphine is also eliminated through the lungs. The poisoning
symptoms reported in grain fumigators, intermittently exposed to about 14
mg/m3 for several hours, fall into three main categories; gastrointestinal
(diarrhea, nausea, epigastric pain, and vomiting), cardiac/respiratory (tightness
of chest, breathlessness, chest pain, palpitations, and severe retrosternal
pain), and central nervous system (headache, dizziness, and staggering gait).
The only symptom in subjects exposed to 0.04 mg/m3 was headache.
Postmortem examination of a child who died because of leakage of phosphine
on a grain freighter revealed myocardial injury, pulmonary edema, and
widespread small-vessel injury. The exposure level was not determined.
Phosphorus pentoxide or phosphoric acid anhydride (P2O5) avidly
absorbs moisture from the air, forming phosphoric acid. Because of its great
affinity for water, it is used as a drying agent. Phosphorus pentoxide is the
primary combustion product when white or red phosphorus is burned in air.
The major environmental transformation is by hydrolysis to phosphoric acid.
Phosphorus pentoxide is locally corrosive and irritating to mucous mem^
branes, eyes, and skin because of its strong dehydrating action .and
exothermic formation of phosphoric acid. Workers noticed but were not
uncomfortable at levels of 0.8 to 5.4 mg/m3, and they tolerated 3.6 to 11.3
mg/m3, with coughing. Only acclimated workers tolerated .levels as high as
100 mg/m3. Phosphorus pentoxide particles in contact with the eyes cause
burns of the eyelids and cornea.
A leading inorganic acid in the U. S. economy, phosphoric acid (H3PO4)
had an estimated production volume of 11,717 tons in 1988. Its major use is in
the manufacture of superphosphate, fertilizers and detergents. Because of its
high production volume and many applications, potential exposure is expected
to be high. In the production of phosphorus munitions, hourly air emissions of
255 Lb/hour were estimated. Washout is the primary fate of phosphoric acid
released to the atmosphere. Phosphoric acid reacts with most environmental
media to yield ubiquitous salts such as calcium, iron, and aluminum
phosphates.
The only information found regarding the acute toxicity of phosphoric acid
in laboratory animal was an oral LD50 in rats of 1,530 mg/kg and a diurnal
LD50 of 2,740 mg/kg for rabbits.
Phosphoric acid also is a skin and eye irritant; it may produce skin burns
and dermatitis. At a concentration of 1 mg/m3, the U. S. Threshold Limit Value-
Time Weighted Average, irritation may occur in unacclimated individuals. Only
one study was found in the published literature on the effects of ingestion of
phosphoric acid and the amount of the acid ingested was not given. However,
the individual experienced some metabolic disorders and a mild burning
sensation in the throat and gastrointestinal tract.
Chlorinated phosphorus compounds are industrially important chemicals
used as intermediates in the manufacture _of pesticides, surfactants, gasoline
additives, Pharmaceuticals, and other compounds. Exposure may occur during
their manufacture and their varied applications. Phosphorus trichloride (PCI3)
is a very corrosive liquid, which reacts exothermically with water, releasing
13
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hydrochloric and phosphoric acid. Acute as well as chronic health effects have
been reported in workers exposed to 11 to 23 mg/m3 and occasionally higher
levels of phosphorus trichloride. The acute effects included a burning
sensation of the eyes and throat, photophobia, chest oppression, cough, and
bronchitis. Chronic exposure for 1 to 2 years produced pulmonary
emphysema. ;
Phosphorus pentachloride (PCI5) is very irritating to all mucous surfaces,
including the lungs. The chemical can cause serious skin burns by an
exothermic reaction with moisture, forming hydrochloric and phosphoric acid.
One report indicated that phosphorus pentachloride may produce kidney
damage.
Phosphorus oxychloride (POCI3) presents similar hazards as phosphorus
trichloride and phosphorus pentachloride. The vapors of this readily volatil-
izing chemical are very irritating to the eyes, skin, and mucous membranes of
animals and humans. Inhalation may cause pulmonary edema. The chemical
produces slowly healing corneal burns in humans. Subchronic exposure of rats
to about 1.34 mg/m3 for 4 months produced a number of effects including
respiratory symptoms, degenerative changes of the brain, mild liver and
kidney dystrophy, and bone abnormalities. The chemical also affected sperm
motility and produced chromosomal aberrations.
Phosphorus sesquisulfide (PsS4) is used in making matches and friction
strips for match boxes. In addition to causing eye and respiratory tract
irritation, it causes contact dermatitis, with both immediate and delayed
hypersensitivity reactions in humans. A number of cases of allergic contact
dermatitis, traced to phosphorus sesquisulfide contained in safety matches,
have been recorded in the literature. In one study, repeated and long-term use
of matches produced recurring episodes of edematous dermatitis,
accompanied by prostration, vertigo, gastrointestinal disturbances, and
loosening of teeth.
No information was found in the published literature on the teratogenic or
reproductive effects of the inorganic phosphorus compounds in animals or
humans or on the carcinogenic potential of these compounds in humans. In
the only studies found on the carcinogenic potential of the inorganic
phosphorus compounds in animals, phosphine did not demonstrate any
carcinogenic effects in rats consuming phosphine-fumigated diets. According
to the U. S. Environmental Protection Agency guidelines on carcinogenicity,
the inorganic phosphorus compounds (phosphine, phosphoric acid,
phosphorus pentoxide, phosphorus pentachloride, phosphorus oxychloride,
and phosphorus sesquisulfide) are classified in Group D, not classifiable as to
human carcinogenicity because adequate animal studies or epidemiological
data are lacking.
14
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2. BACKGROUND INFORMATION
This review provides a brief summary of the available information
concerning the potential health effects associated with exposure to elemental
phosphorus and phosphorus compounds. Acute and chronic health effects are
addressed, including systemic toxicity, genotoxicity, and reproductive and
developmental effects. This report also briefly reviews physical and chemical
properties, sources, environmental fate, and concentrations found in air, as a
background for placing the health effects discussion in perspective. Because
of the large number of phosphorus compounds, this report will focus on only
elemental phosphorus and a group of inorganic phosphorus compounds
selected because of the potential for exposure from their manufacture and use
and/or their known toxicity to humans and other mammals.
2.1 Chemical Characterization and Measurement
2.1.1 Elemental Phosphorus
Phosphorus (CAS No. 7723-14-0), a nonmetallic essential element, has
the empirical and molecular formula P. About 60 years ago, three major
allotropic modifications of elemental phosphorus were recognized; white (or
yellow when impure), red, and black. White phosphorus is the best known
form and of greatest commercial importance. It is the most volatile and
reactive form of the solid, igniting spontaneously in air. It is soluble in organic
solvents but shows only limited solubility in water. At room temperature, white
phosphorus exists as the alpha form, consisting of cubic crystals containing P4
molecules. At -79.6 °C it converts to hexagonal crystals (Windholz et al., 1983).
Red phosphorus is very insoluble and is more stable, although on exposure to
air it reacts slowly with oxygen and water vapor. It exists in a number of
different polymeric modifications which often coexist in a given preparation
(Van Wazer, 1982). Black phosphorus, a crystalline amorphous solid
resembling graphite, is the least known form of phosphorus. It is insoluble in
most solvents and thermodynamically the most stable of the phosphorus
allotropes.
Analytical methods for the detection of white phosphorus in air include:
neutron activation analysis (Carlton and Lehman, 1971), flame emission
photometry (Prager and Seitz, 1975), and colorimetry (Rushing, 1962).
Analytical techniques which are not specific for elemental phosphorus or other
phosphorus compounds but determine the total amount of phosphorus in a
sample include X-ray spectroscopy, emission spectroscopy, and spark source
mass spectrometry (Wasti et al., 1978).
In water, suitable analytical techniques include neutron activation (Lai and
Rosenblatt, 1977a), flame emission photometry (Prager and Seitz, 1975), and
gas-liquid chromatography (Addison and Ackman, 1970). 2.1.2 Inorganic
Phosphorus Compounds.
15
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2.1.2 Inorganic Phosphorus Compounds
Phosphine (PH3) (CAS No. 7803-51-2), a toxic gas with an odor of
decaying fish, ignites spontaneously in air in the presence of traces of
diphosphane (P2H4) and other impurities (Sax, 1986). It is only slightly soluble
in water but will combine violently with oxygen and the halogens (Windholz et
al., 1983). ;
Analytical methods for the detection of phosphine in air include gas
chromatography (Berck et al., 1970; Bond and Dumas, 1982), gas
chromatography-mass spectrometry and electrochemical/coulometric methods
(Verstuyft, 1978), colorimetry/spectrophotometry (Dechant et at., 1966), and
column/paper chromatographic methods (Muthu et al., 1973).
Phosphorus pentoxide, also known as phosphoric anhydride (PaO5) (CAS
No. 1314-056-3), is a stable white solid which exists in several crystalline or
amorphous modifications. It readily absorbs moisture from the air, forming
phosphoric acid by exothermic hydrolysis (Windholz et al., 1983; Beliles,
1981; Boenig et al., 1982). The analytical method used for the determination of
phosphorus pentoxide in air is colorimetry (Wasti et al., 1978).
Phosphoric acid or orthophosphoric acid (H3PO4) (CAS No. 7664-38-2)
exists as a clear syrupy liquid or as deliquescent crystals (Heimann, 1983). It
is a tribasic acid, stronger than acetic, oxalic, or silicic acid, but weaker than
sulfuric, nitric, hydrochloric, or chromic acid. The most concentrated
commercial form of this compound contains 85 percent phosphoric acid
(Beliles, 1981). Analytical methodology for the determination of phosphoric
acid in air are colorimetry (National Institute of Occupational Safety and
Health, 1977) and colorimetry/spectrophotometry (Wasti et al., 1978).
Phosphorus trichloride (PCI3) (CAS No. 7719-12-2), a colorless fuming
liquid, reacts exothermically with water, releasing hydrochloric and phosphoric
acid. It volatilizes at room temperature (Beliles, 1981). Phosphorus trichloride
is an extremely corrosive liquid, forming phosphine upon heating (Heimann,
1983). Colorimetry is the analytical technique used for the quantitation of
phosphorus trichloride in air (National Institute for Occupational Safety and
Health, 1979).
Phosphorus pentachloride (PCI5) (CAS No. 10026-13-8) is a yellow,
fuming, crystalline mass with a pungent unpleasant odor. It reacts with water,
hydrolyzing to phosphoric acid and hydrochloric acid (Windholz et al., 1983).
When heated, it produces phosphorus trichloride and chlorine (Beliles, 1981).
The analytical method used for the determination of phosphorus pentachloride
in air is colorimetry (National Institute for Occupational Safety and Health,
1979).
Phosphorus oxychloride or phosphoryl chloride (POCI3) (CAS No. 10025-
87-3) is a clear, fuming liquid with a pungent odor. It is stable below 300 °C
and yields phosphoric acid upon hydrolysis (Boenig et al., 1985). When
heated to decomposition it emits fumes of Cl~, POX, and NOX (Sax, 1984).
Phosphorus sesquisulfide (P3S4) (CAS No. 1314-85-8) is a crystalline
yellow solid. It is insoluble in cold water but will decompose in hot water
(Heimann, 1983).
2.2 Production and Uses
2.2.1 Elemental Phosphorus
Domestic production capacity of elemental phosphorus as of 1988 was
approximately 376,000 metric tons (SRI International, 1988). As of 1988,
16
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elemental phosphorus was produced domestically by 5 companies. Table 2-1
shows the producers and their annual production capacities.
White phosphorus is produced by several methods. The most important
means of production is by the electric-arc process. Phosphate rock is ground,
formed into pellets, and smelted with coke and silica in an electric furnace to
produce elemental phosphorus vapors (U. S. Environmental Protection
Agency, 1982; Van Wazer, 1982). The white phosphorus vapors are then
cleaned and collected by passing through an electrostatic precipitator and
condenser (Van Wazer, 1982). White phosphorus is also produced as an
intermediate in the thermal process for phosphoric acid production
(Lowenheim and Moran, 1975).
Red phosphorus is produced by heating white phosphorus to
approximately 400°C in the absence of air or in an inert atmosphere
(Lowenheim and Moran, 1975). Black phosphorus is produced from white
phosphorus under pressure (Hawley, 1 981 ).
Most of the white phosphorus produced is ultimately utilized in the
production of phosphoric acid and phosphates (Lowenheim and Moran, 1975).
It is also used in the production of phosphorus sulfides, phosphorus halides,
phosphorus pentoxide, and red phosphorus. It is used in ferrous metallurgy, in
insect and rodent poisons, and in the manufacture of artificial fertilizers,
semiconductors, and electroluminescent coatings (Sittig, 1985). The military
uses include the production of mortar and artillery shells and hand and rifle
grenades. While white phosphorus is a commercially important chemical, red
phosphorus is a specialty item. It is a component of the box coatings of safety
matches and is used in the manufacture of fireworks (Van Wazer, 1982). There
are no current uses for black phosphorus (Hawley, 1981).
2.2.2 Inorganic Phosphorus Compounds
Phosphine is not considered an important industrial chemical (Beliles,
1981). Commercially, phosphine is produced by the reaction of aluminum
phosphide with water or by an electrolytic process whereby nascent hydrogen
reacts with elemental phosphorus (Boenig et al., 1982). It is used as a grain
fumigant, as a doping agent for electronic components, in chemical synthesis
(American Conference of Governmental Industrial Hygienists, 1 980), and in the
control of rodents and moles by placing the compound in outdoor burrows and
closing the openings (Hayes, 1982).
Phosphorus pentoxide is made commercially by burning phosphorus in a
stream of air. Estimated U. S. production of phosphorus pentoxide in 1 985 was
6,300 thousand tons (Toxnet, 1 989). Phosphorus pentoxide has a great af-
Table 2-1. United States Producers of Elemental Phophorus (1988)
Company
Location
Annual Capacity
(thousands of
metric tons)
FMC Corporation
Monsanto Company
Occidental Petroleum Corporation
Stauffer Chemical Company
Pocatello, ID 137
Soda Springs, ID 95
Columbia, TN 57
Mount Pleasant, TN 45
Silver Bow, MN 42
Capacity data are on a P^ basis.
Source: SRI International (1988).
17
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finity for water and is used in this capacity as a drying agent (Beliles, 1981). It
is also used in the manufacture of phosphorus oxychloride, acrylate esters and
surfactants, as a catalyst in air blowing of asphalt, and in other applications
(Boenig etal., 1982).
Phosphoric acid is manufactured by the wet process or the furnace
(thermal) process. The wet process acid, produced directly from phosphate
ores, has a high production volume, low cost, and low purity. It is used mostly
for the production of fertilizers. Phosphoric acid manufactured by the furnace
or thermal process is produced from elemental phosphorus. It is produced in
much smaller quantities for uses other than fertilizer applications, such as
metal treatment, refractories, catalysts, and food and beverages (Hudson and
Dolan, 1982). Estimated production of phosphoric acid in the United States for
1987 was 10,473 thousand tons. Estimated production in 1988 was 11,717
thousand tons, an increase of 11.9 percent from 1987 (Reisch, 1989).
The single greatest use of phosphoric acid is in the manufacture of
phosphate salts, with superphosphate fertilizers representing the single largest
market (Hudson and Dolan, 1982). Phosphoric acid is used in the manufacture
of detergents, activated carbon, animal feed, ceramics, dental cement,
Pharmaceuticals, soft drinks, gelatin, rust inhibitors, wax, and rubber latex. It is
used for electropolishing, engraving, photoengraving, lithograving, metal
cleaning, sugar refining, and water treating (Sittig, 1985).
Phosphorus trichloride is manufactured by the direct union of phosphorus
and chlorine. Phosphorus trichloride is one of the largest volume primary
products of phosphorus, second only to phosphoric acid and its salts. The
estimated production capacity for phosphorus trichloride produced in the
United States as of January 1988 was 169 thousand tons (SRI International,
1988). Phosphorus trichloride, reacting readily with oxygen, sulfur, chlorine,
and water, serves as an intermediate in the manufacture of phosphorus
oxychloride, phosphorus sulfochloride, phosphorus pentachloride, and
phosphorous acid (H3P03) (Boenig et al., 1982). It is used as an intermediate
in the preparation of pesticides, surfactants, gasoline and lubricating oil
additives, plasticizers, and dyes, as a catalyst, and as an ingredient in textile
finishing agents (American Conference of Governmental Industrial Hygienists,
1980; Chemical Economics Handbook, 1983; Windholz et al., 1983).
Phosphorus pentachloride is made from phosphorus trichloride and
chlorine or by burning elemental phosphorus in the presence of excess
chlorine (Boenig et al., 1982). It is used for replacing hydroxyl groups by
chlorine, particularly for converting acids into acid chlorides (Windholz et al.,
1983).
Phosphorus pentachloride is also used in the manufacture of agricultural
chemicals, chlorinated compounds, gasoline additives, plasticizers and surfac-
tants, and Pharmaceuticals (Sittig, 1985).
Phosphorus oxychloride is manufactured by oxidizing phosphorus
trichloride or by reacting pentachloride with pentoxide. The estimated
production capacity for phosphorus oxychloride produced in the United States
as of January 1988 was 66 thousand tons (SRI International, 1988).
Phosphorus oxychloride is used in the manufacture of many pesticides and
Pharmaceuticals, as well as plasticizers, gasoline additives, and hydraulic fluid
(Sittig, 1985). In the manufacture of pesticides, it is extensively used as an
intermediate for alkyl and aryl orthophosphate triesters (Windholz et al., 1983).
Phosphorus sesquisulfide is produced by direct union of the elements.
The temperature of the sulfur and the quantity of phosphorus determine
whether phosphorus sesquisulfide or the pentasulfide are formed.
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Sesquisulfide is purified by vacuum distillation or washing with water or
sodium bicarbonate solution (Boenig et al., 1982).
2.3 Environmental Release and Exposure
Although phosphorus is the twelfth most abundant element in nature it
does not occur in the free state but instead is found in the form of phosphates
in the minerals fluorapatite, vivianite, chlorapatite, and wavelite, and in
phosphate rock. It occurs in all fertile soils and in small quantities in granite
rocks (U. S. Environmental Protection Agency, 1982). Although natural
discharge of phosphorus in the environment may occur (weathering and
leaching of phosphate rock, pollen, plant residue, and wild animal and bird
waste), phosphorus is found in the environment almost exclusively as the
result of anthropogenic sources (mining, processing, and the manufacture,
use, and disposal of phosphorus and phosphorus-containing products, coal
combustion, and forest fires) (U. S. Environmental Protection Agency, 1982;
Mishra and Shukla, 1986; Raison et al., 1985).
2.3.1 Elemental Phosphorus
Only limited information was found in the published literature on the actual
ambient levels of elemental phosphorus. However, estimates of phosphorus
releases as the result of mining, processing, and the manufacture, use, and
disposal of phosphorus-containing products have been made by several
researchers.
Lum et al. (1982) reported elemental phosphorus levels ranging from 370
to 2,460 yg/g in the form of particulate matter in the vicinity of St. Louis,
Missouri. Berkowitz et al. (1981) estimated that emissions of elemental
phosphorus from the manufacture of phosphorus munitions could be as great
as 0.5 mg/m3/hour (worst-case upper limit), with a more likely upper limit of
0.5 iig/m3/hour.
These authors also estimated community exposure as a result of
deployment of white phoshorus/felt and red phosphorus/butyl rubber
screening smokes in training or testing field activities. Estimated exposures
ranged for 146 mg/m3 (as P2O5) 100 m downwind from deployment to 0.963
mg/m3, 5,000 m downwind. Community exposures are not expected to be
severe at a distance greater than 300 m. However, particularly sensitive
individuals may encounter respiratory irritation at distances of about 5,000 m.
In 1979, the U. S. Environmental Protection Agency estimated coal
combustion to be the largest single source of phosphorus air emissions,
accounting for about 23 percent of the total national air emissions of
phosphorus. The second largest source (about 20 percent) was phosphate
rock mining and beneficiation activities. The third was iron manufacture (about
11 percent). Fuel oil combustion ranked fourth (7 percent), followed by the
manufacture of animal feed-grade calcium phosphates (6 percent). All other
estimated source quantities of phosphorus in air. emissions were less than 5
percent. Refer to Table 2-2 for emission factors.
White phosphorus may enter the aquatic environment as phossy water
which contains dissolved and colloidal phosphorus as well as larger
suspended particles and oxides of phosphorus. Phossy water is generated
wherever white phosphorus is manufactured or stored underwater (Sullivan et
al., 1979).
Following the opening of a plant producing elemental phosphorus in Long
Harbour, Placentia Bay, Newfoundland, phossy water was discharged to
adjacent waters. Although the levels of phosphorus released were not given,
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Table 2-2. Estimated Emission Factors for Point Source Emission of
Phosphorus to the Environment
Discharged
Waste Water
(kg P/MT product)
Industry or Activity Description
Air Emission
(kg P/MT
product)
Phosphate rock mining and beneficiation:
Eastern operations
Western operations
0.094
0.180
0.005
Industrial Manufacturing:
Elemental phosphorus
Dry process phospheric acid
Phosphorus pentoxides
Phosphorus trichloride
Phosphorus oxychloride
Phosphorus pentasulfide
Sodium phosphate
Feed-grade calcium phosphates
Phosphorus based detergents
Direct acid treatment of metal surfaces
0.64
0.57
8.50
10.8
4.74
15.14
2.0
2.4
0.007
0.12
0.15
0.044
0.024
0.05
0.05
0.034
0.004
0.17
0.029
0.044
Agricultural consumption of phosphate rock:
Wet-process phosphoric acid
Superphosphoric acid
Normal superphosphate
Triple superphosphate
Ammonium phosphate
Defluorinated phosphate rock
(livestock and poultry feeds)
Animal feed-grade calcium phoshates
0.166
0.007
0.47
0.35
0.149
2.2
2.6
0.0006
0
0.0003
0.00002
0.002
0.33
0.026
Source:, U. S. Environmental Protection Agency (1979).
concentrations of approximately 5,000 parts per million (ppm) were found in
the sediments in many areas of the bay, except for one location approximately
1.5 miles from the phosphorus outfall that had a concentration of
approximately 1 ppm.
Before water recycling 'measures were implemented, concentrations of
16.0 to 53.4 mg/L of white phosphorus have been reported in effluents at the
Pine Bluff Arsenal, Arkansas, from the manufacture of white phosphorus
munitions employing the wet-fill method (Pearson et al., 1976). Lai et al. (1979)
reported concentrations of white phosphorus in Yellow Lake, Pine Bluff
Arsenal, ranging from 0.005 to 0.010 ng/L, while the Arkansas River contained
0.003 to 0.004 ug/L.
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Inorganic Phosphorus Compounds
Exposures to phosphine may occur when acid or water comes in contact
with metallic phosphides such as aluminum phosphide or calcium phosphide.
These two phosphides, pesticides used on grain, release phosphine during
fumigation. It may also evolve during the generation of acetylene from impure
calcium carbide, metal shaving, sulfuric acid tank cleaning, rust proofing, and
ferrosilicon, phosphoric acid, and elemental phosphorus explosive handling
(Sittig, 1985). Phosphine is also produced from incomplete combustion of
white phosphorus/felt and from the solid phase oxidation of red
phosphorus/butyl rubber as a function of relative humidity (Spanggord et al.,
1985). Accidental release of phosphine was reported by Gould et al. (1986)
when a 20-foot shipping container containing aluminum phosphide aboard a
ship exploded. A survey of the ship found 40 to 60 ppm of phosphine in one
hold. Devai et al. (1988) showed that phosphine is released from sewage
treatment plants and from sediments of shallow waters. They estimated that
about 5 g of phosphorus/day is released as phosphine from a tank settling
2,000 m3/day of raw sewage.
Carpenter et al. (1978) list phosphorus pentoxide as a secondary air
pollutant which may result from the open burning of waste munitions. They
also cite a study that attempted to derive typical daily emissions for large-
scale open burning of several explosives by extrapolation from laboratory
tests. Open burning of 3.8 tons of the waste munition PBX-9494 was estimated
to result in the daily release of 49 pounds of phosphorus pentoxide. Trace
quantities of phosphorus pentoxide have also been identified in atmospheric
emissions from electric arc alloy and steel melting operations (Bates and
Scheel, 1974).
The principal atmospheric emission from the manufacture of phosphoric
acid by the thermal process is particulate phosphoric acid mist (U. S.
Environmental Protection Agency, 1980a,b). The two major components of this
process include combustion of elemental phosphorus to produce phosphorus
pentoxide and hydration of the pentoxide to produce the acid. Estimated
particulate emissions from a typical thermal process phosphoric acid plant (as
100 percent phosphorus pentoxide) are 1.04 kg/hour (2.3 Lb/hour) or 8.2
Mg/year (9.1 tons/year) (U. S. Environmental Protection Agency, 1980a).
Phosphoric acid is the major phosphorus compound released in stack
emissions during the production of phosphorus munitions (Berkowitz et al.,
1981). At Pine Bluff Arsenal, Arkansas, air emissions of 255 pounds of
phosphoric acid/hour occurred under normal operations of Ventura scrubbers,
and emissions as great as 5,100 Lb/hour could occur during improper
scrubbing operations.
Emissions from a British plant manufacturing sulfuric acid, phosphoric
acid, and sodium tripolyphosphate, measured as deposited phosphates
ranged from 636 mg/L in the immediate vicinity of the plant to 1.8 mg/L at a
sampling site 2.5 km distant (Harrison, 1983).
No information was located in the published literature on the
environmental release of or exposure to phosphorus trichloride, phosphorus
pentachloride, phosphorus oxychloride, or phosphorus sesquisulfide.
21
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2.4 Environmental Fate
2.4.1 Elemental Phosphorus
In air, elemental phosphorus in the vapor phase reacts rapidly with
atmospheric oxygen to produce phosphorus oxides (Spanggord et al., 1985).
According to the findings of Dainton and Bevington (1946), white phosphorus
inflames at most environmental pressures and temperatures greater than 5°C;
hence, it is not likely that white phosphorus will persist in air. White
phosphorus/felt was found to react rapidly with air (t1/2 = about 5 minutes),
while red phosphorus/butyl rubber was more persistent in air (t1/2 = 1.8
years) (Spanggord et al., 1985).
The majority of phosphorus compounds released and dispersed in the air
from the production and use of military screening smokes will be rained out as
phosphoric acid or phosphates and deposited on land and in aquatic systems
(Berkowitz et al., 1981). Anaerobic sediments and soil can serve as sinks of
white phosphorus that, in turn, can serve as long-term sources of mobilization
into the environment (Lai, 1981; Spanggord et al., 1985).
After release into waterways, white phosphorus rapidly oxidizes and
hydrolyzes. Volatilization is also a potential route of loss. White phosphorus
appears to be resistant to anaerobic degradation (Spanggord et al., 1985).
Dissolved oxygen concentration, temperature, pH, metals, and sediment
particles will affect the transformation of phosphorus in water (Spanggord et
al., 1985; Zitko et al., 1970). Oxidation is the primary route of loss from
sediments.
In soils, oxidation is also the predominant route of degradation of white
phosphorus. Biotransformation does not appear to be significant. Some loss
from soil to aquatic systems can occur through leaching, but is probably not
significant. Because of the limited availability of oxygen in soils and the
formation of oxides, which impede further oxidation, white phosphorus is likely
to persist when buried in soil (Spanggord et al., 1985).
2.4.2 Inorganic Phosphorus Compounds
Phosphine is not expected to persist in the environment (Spanggord et al.,
1985). Because of its high vapor pressure (1 x 104 torr) and low water
solubility, it will rapidly volatilize into the atmosphere. In the atmosphere,
oxidative reactions with ozone and hydroxyl radical will limit its persistence to
half-lives of 8 and 5 hours, respectively. In the presence of sunlight,
incompletely understood interactions with tropospheric agents will yield a half-
life of 2 to 3 hours (Spanggord et al., 1985).
Phosphorus pentoxicle in the atmosphere is readily hydrolyzed to yield
phosphoric acid (Spanggord et al., 1983; Berkowitz et al., 1981). Phosphoric
acid in the atmosphere will be rained out and deposited on land and in aquatic
systems (Berkowitz et al., 1981).
No information was found on the environmental fate of phosphorus
trichloride, phosphorus pentachloride, phosphorus oxychloride, or phosphorus
sesquisulfide.
2.5 Environmental Effects
2.5.1 Elemental Phosphorus
Abiotic effects resulting from release of white phosphorus to aquatic
systems include increased acidity, decreased dissolved oxygen, and
22
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increased sedimentation. Increased acidity and decreased dissolved oxygen
could result from the oxidation of phosphorus to hypophosphorous,
phosphorous, and phosphoric acids (Lai and Rosenblatt, 1977b). Peer (1972)
noted local changes in sediment characteristics consisting of substantially
increased deposition of fine particulates from the area of effluent discharge of
a phosphorus production plant.
Field and laboratory studies indicate that white phosphorus is toxic to
waterfowl and fish. Wild mallard ducks feeding in areas .of phossy water
discharge have ingested lethal quantities of elemental phosphorus (Coburn et
al., 1950). In a series of experiments conducted with black and mallard ducks
there was a marked individual variation in tolerance, but a single dose of 3
mg/kg of body weight resulted in death in 6 to 33 hours in all ducks studied.
Acute poisoning caused depression, followed by leg weakness, violent
convulsions, and death. Birds suffering from chronic poisoning steadily lost
weight and showed signs of paralysis. All poisoned birds displayed fatty
degeneration of muscle tissue, liver, and kidneys.
Much of the' available information concerning the toxicity of white
phosphorus to aquatic species derives from studies initiated in response to a
massive fish kill caused by wastewater discharged from the ERGO
phosphorus production plant in Long Harbour, Placentia Bay, Newfoundland.
Hodder et al. (1972) reported an 80 percent decline in the abundance of
Clupea harengus (herring) in Placentia Bay over a 1-month period. Mortalities
resulted also in a decreased yield in nearby St. Mary's Bay, where herring
migrate to reproduce. Massive herring mortalities were observed up to 60
miles from the localized pollution site in Placentia Bay (Zitko et al., 1970).
In,static tests with fish, Lepomis macrochirus (bluegill sunfish) was the
most sensitive species with a 96-hour LC50 of 6 ng/L, and Ictalurus punctatus
(channel catfish) was the least sensitive with a 96-hour LC50 of 73 pg/L. In
dynamic bioassays, fish were even more sensitive to white phosphorus. The
LC50 for bluegill was 2.4 pg/L and that for channel catfish 19 pg/L (Bentley et
al., 1978)., The LT50 for Salvelinus fontinalis (brook trout) exposed to 0.5 pg/L
was 121 hours (Fletcher et al., 1970) and that for Salmo salar (Atlantic salmon)
exposed to 0.79 pg/L was 195 hours (Fletcher and Hoyle, 1972). Incipient
levels (lethal concentration for 50 percent mortality from long exposure)
ranged from 0.6 ug/L for bluegill (Bentley et al., 1978) to 18 pg/L for Atlantic
salmon (Zitko et al., 1970). Maddock and Taylor (1976) measured the acute
toxicity of dissolved elemental phosphorus to cod (Gadus morhua). The 48-
hour LC50 was 14.4 pg/L and the incipient lethal level was approximately 1.0 to
2.0 ug/L. The toxic effect of phosphorus in herring, salmon, and lobster was
irreversible and probably cumulative (Zitko et al., 1970). In flow-through
studies of critical life stage, Bentley et al. (1978) found that the most sensitive
life stages for Pimephales promelas (fathead minnow) are 30-day-old and 60-
day-old fry.
Chronic exposure of fathead minnow to a white phosphorus concentration
of 1.5 pg/L reduced survival in all fish. By day 150, the growth of all fish
surviving exposures to 1.5 or 3.4 pg/L was so stunted that internal and external
evidence of sexual maturity was absent. Even at 0.4 pg/L, the lowest
concentration tested, hatchability was significantly reduced (Bentley et al.,
1978).
Several investigators reported cardiovascular changes in fishes associated
with phosphorus exposure (Pippy et al., 1972; Zitko et al., 1970; Fletcher et al.,
1970; Fletcher and Hoyle, 1972). The symptoms included externally visible
redness, hemolysis, low hematocrits, and pale internal organs and blood. The
lowest hematocrits were associated with long, low-level exposure. Hemolysis
23
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was observed in fish as well as in Homerus americanus (lobster). Substantial
variation of response existed'among species. Herring was the most severely
affected aquatic species in the natural environment. Histological changes
included damage to the gill, kidney, liver, and spleen. In lobster, exposure to
white phosphorus caused degeneration of the hepatopancreas and antennal
gland and coagulation of the blood.
Bioaccumulation of phosphorus is rapid, with the greatest uptake in the
liver and muscle of fish and the hepatopancreas of the lobster;
however.depuration occurs within seven days after exposure. Uptake appears
to be positively correlated with lipid content. Reported bioconcentration factors
range from 10 to 15,000 in fish, 10 to 1,267 in invertebrates, and is 22 in
seaweed (Bentley et al., 1978; Dyer et al.; 1970; Maddock and Taylor, 1976;
Fletcher, 1971). Fletcher (1974) reported the biologic half-life of yellow
phosphorus in tissues of Atlantic cod (Gadus morhua) exposed in seawater.
They were 4.71, 6.16, and 5.27 hours for blood, muscle, and liver,
respectively. Shorter half-lifes were observed in Atlantic Salmon (Salmo salar),
ranging from 0.9 hours in the liver to 1.3 hours in gills.
In contrast to the relatively rapid half-life of phosphorus in tissue of living
cod, Dyer et al. (1972) found a slow rate of phosphorus degradation in muscle
tissue of processed dead cod. Using white muscle of Atlantic cod (Gadus
morhua) which had been exposed in vivo to elementary phosphorus, the
authors found that phosphorus was remarkably stable during processing of the
fish by commercial procedures. Icing of both round fish and fillets, freezing
and thawing, salting, and cooking did not produce a product that was
sufficiently safe for human consumption. The various methods produced some
decrease in the initial phosphorus content, but in almost all of the samples,
about 40 percent or more remained.
In chronic studies with macroinvertebrates, exposure of water fleas
(Daphnia magna) to 8.7 pg/L of phosphorus significantly reduced survival.
Concentration of <6.9 ng/L did not affect survival or the number of young
produced by first and second generations (Bentley et al., 1978).
Limited studies on the toxicity of white phosphorus to algae reveal
variable results and no exposure-response relationship (Bentley et al., 1978;
Poston et al., 1986). The growth of two species of blue-green algae, Anabaena
flos-aquae and Microcystis aeruginosa, was stimulated, but the growth of
Navicula pelliculosa, a diatom, and Selenastrum capricornutum, a green alga
was inhibited.
Field studies indicate that effluents containing white phosphorus adversely
affect the receiving aquatic systems. Releases have altered the structure of
benthic communities by decreasing diversity and by selective mortality.
Pearson et al. (1976) reported that phosphorus and phosphate species were
significant factors governing the distribution of benthic organisms in Yellow
Lake, Pine Bluff Arsenal, Arkansas. Surveys of Placentia Bay, Newfoundland,
showed that the only live benthic species collected in the vicinity of the outfall
was Modiolus modiolus (sea mussel). A more distant location showed reduced
biomass and diversity. Scallop mortalities were observed 1,000 m from the
pipe. Fve percent of a population of sand dollars (Echinarachnius parma) were
surviving in an area where 90 percent would normally be alive (Peer, 1972).
2.5.2 Inorganic Phosphorus Compounds
The only study found in the available literature on the environmental
effects of the inorganic phosphorus compounds was a study designed to
determine the effect of acidity on bluegill sunfish. In that study Ellgaard and
Gilmore (1984) exposed bluegill sunfish to various concentrations of
24
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phosphoric acid. No mortality was observed from pH 5.0 to 3.5. When the pH
reached 3.25 and 3.0, the mortality was 13 and 100 percent, respectively. At
sublethal concentrations, the bluegill became hypoactive.
25
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3. HEALTH EFFECTS
3.1 Pharmacokinetics and Metabolism
There are only limited quantitative data on the pharmacokinetics and
metabolism of elemental and inorganic phosphorus compounds. There are,
however, studies which indicate that these compounds are absorbed. Most of
these studies deal with the toxicological properties of elemental phosphorus
and inorganic phc-sphorus compounds and are discussed elsewhere in this
document.
3.1.1 Elemental Phosphorus
Only one study was found on the absorption • of inhaled elemental
phosphorus. High levels of radioactivity were detected in the lungs and
digestive tract of mice immediately after exposure for 1 hour to an aerosol
containing 5 mg/m3 32p.red phosphorus. Radioactivity was retained in the
lungs for at least 10 days, but the digestive tract was free from phosphorus
within ,48 hours. Radioactivity was not detected in systemic organs and it was
therefore difficult to determine whether the phosphorus was actually absorbed
(Dalhamn and Holma, 1959).
After administering rats 0.75 mg of radiolabelled phosphorus by gastric
intubation, Ghoshal et al. (1971) reported that within 2 to 3 hours following
administration approximately 65 to 70 percent of the administered dose was
recovered in liver, and approximately 40 percent remained after 24 hours. The
recovery from other organs 2 hours after exposure was as follows: blood, 12
percent; kidneys, 4 percent; and spleen, pancreas, and brain, 0.4 percent
each. Approximately 82 percent of the administered dose was absorbed within
2 hours. Lee et al. (1975), after administering rats 0.1 percent 32p.whjte
phosphorus in peanut oil by gastric intubation, reported that about 60 to 65
percent of the oral dose was absorbed within 24 hours. A large amount of
radioactivity was recovered in the liver, with significant amounts also
recovered from blood and skeletal muscle.
Cameron and Patrick (1966) demonstrated that phosphorus is absorbed
after administering 0.5, 3.5, and 20.0 mg of 32p-white phosphorus to mice,
rats, and rabbits, respectively, by gastric intubation. After 48 hours, the
distribution of radiolabelled phosphorus was fairly uniform across species. The
relative distribution was blood > feces > bowel > liver > kidney > spleen
> lung a heart. No quantitative data on the amounts of absorbed phosphorus
were given.
Subramanian et al. (1985) determined the phosphorus content in some
autopsy samples of human liver, kidney cortex, and kidney medulla from resi-
dents of Kingston and Ottawa, Ontario. There were no significant differences
between the two communities and the values were considered to be within the
normal range. Liver and kidney (cortex and medulla) samples contained 1,800
to 2,800 and 1,300 to 2,200 mg/kg wet weight of phosphorus, respectively.
27
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Phosphorus appeared to accumulate preferentially in the liver. The median
phosphorus content in kidney was about 66 percent of that in liver.
Though white phosphorus is readily absorbed from the gastrointestinal
tract, red phosphorus is considered nontoxic by the oral route because of poor
absorption (Berkowitz et al., 1981). No information was found indicating the
actual extent of red phosphorus absorption.
In a study on dermal absorption, Walker et al. (1969) burned white
phosphorus pellets (25 mg) on the skin of a young pig. The residue on the
skin was 24 percent acids of phosphorus, 93 percent of which was
orthophosphoric acid. Approximately 2.71 mg of phosphorus penetrated the
skin as orthophosphoric acid. However, phosphorus did not penetrate the skin
beyond 2 mm of the surface.
Whiteley et al. (1953) studied the uptake of radioactive phosphorus by
rabbit skin. Rabbits were injected intravenously with 75 jiCi/kg of 32P and killed
at various intervals between 5 minutes and 72 hours after injection. Within 5
minutes after injection, radioactivity was taken up by the skin, with more taken
up by the areas of active hair growth than by quiescent areas. This difference,
which was maintained throughout the observation period, was attributed to the
greater incorporation of 32P in nucleic acids in the areas of active hair growth.
In humans, no convincing evidence was found by Walker et al. (1947) and
Summerlin et al. (1967) that phosphorus is absorbed dermally in sufficient
quantities to cause systemic effects. These studies are discussed in more
detail in Section 3.8.1. Hughes et al. (1962) did not find significant differences
in mean hematological and blood chemistry values between phosphorus-
exposed workers and control subjects, although systemic changes were
observed in some cases of chronic exposure to white phosphorus fumes.
Increases in serum inorganic phosphate levels are not always
demonstrated immediately after acute ingestion of elemental phosphorus. In
most cases normal inorganic phosphate levels and sometimes
hypophosphatemia are observed rather than hyperphosphatemia. McCarron
et al. (1981) reported that serum inorganic phosphate levels dropped to 1.5
and 1.8 mg/mL on the day of and the fourth day after ingestion of elemental
phosphorus, respectively. Normal values range from 3.0 to 4.5 mg/mL
(Berkow, 1982). In similar cases an increase in inorganic phosphate levels
was not observed until 15 days and 4 or 5 days after intoxication (Diaz-Rivera
et al., 1950). The authors suggested that the delayed hyperphosphatemia
may be due to accumulation of phosphorus in tissues, especially in bone, and
that it is later mobilized by a change in the acid-base balance. Winek et al.
(1973) reported that the phosphorus content in liver was 0.049 mg percent and
0.78 mg percent in patients who died 8 and 22 hours, respectively, after
ingestion of elemental phosphorus. In another patient who died within 3.5
hours, the phosphorus content in the kidney was 0.095 mg percent.
Phosphorus is eliminated through urine and feces (Cameron and Patrick,
1966; Lee et al., 1975). Forty-eight hours after dosing mice, rats, and rabbits
by gastric intubation with 32P-v/h\te phosphorus, radioactivity appeared in
urine of rabbits but not in mice and rats. Radioactivity was also found in feces
of all three species (Cameron and Patrick, 1966). Lee et al. (1975), however,
found that 17.1 percent of an orally administered dose of 32P-white
phosphorus appeared in urine of rats 4 hours after dosing (Table 3- 1). At 1
and 5 days, 34.5 percent and 46.7 percent, respectively, appeared in urine.
The fecal content of 32P-white phosphorus was 2.0 percent, 16.6 percent, and
33.0 percent at 4 hours, 1 day, and 5 days, respectively. The authors did not
determine whether the radioactivity in fecal material was due to direct
elimination from the gastrointestinal tract or was the result of biliary excretion.
28
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Table 3-1. Distribution and Excretion of Radioactivity in Rate Receiving
szp-White Phosphorus
Percent of Administered Dose
Gastrointestinal tract
plus contents
Feces
Whole blood*
Urine
Liver
Kidneys
Spleen
Brain
Lungs
Skeletal muscleb
Recovery
4 Hours
57.0 ± 3.4°
2,0 ± 1.0
6.1 ± 1.1
17.1 ± 2.2
16.1 ± 4.6
0.7 + 0.2
0.1 ± 0.0
0.1 + 0.0
0.4 ± 0.0
4.0 ± 0.0
98.6 ± 5.0
1 Day
15.3 ± 4.0
16.6 + 3.8
4.1 ± 0.5
34.5 ± 6.1
16.9 ± 0.7
0.8 ± 0.1
0.1 ± 0.0
0.1
0.3 ± 0.1
5.5 ± 0.2
94.0 ± 3.3
5 Days
1.7 + 0.2
33.0<*
1.7 ± 0.0
46. 7^
6.3 ± 0.3
0.4 i 0.0
0.1
0.1
0.2 ± 0.0
6.0 ± 0.6
6.0
aBased on 7.0 percent of the body weight.
bBased on 40 percent of the body weight
cMean ± S.E. of three rats.
^Pooled samples from three rats.
Source: Lee et al. (1975).
Thin layer chromatography of the urine from rats administered 32P-white
phosphorus separated two major radioactive components: one was inorganic
phosphate and the other was a more nonpolar component suggestive of
organic phosphate. Analysis of liver extracts also demonstrated two classes of
metabolites with properties similar to those found in the urine (Lee et al.,
1975).
3.1.2 inorganic Phosphorus Compounds
The effects of phosphine on numerous organs suggest a wide tissue
distribution (Hayes, 1982). Nevertheless, the chemical was not detected in
tissues of fatal cases of phosphine poisoning (Harger and Spolyar, 1958).
Harger and Spolyar (1958) cite other investigators who suggested that
phosphine is readily metabolized to phosphates, thereby simply adding to the
pool of existing phosphates. The tissues from two fatal cases of phosphine
poisoning reportedly contained lower oxides of phosphorus (Reinl, 1956).
The only other study found in the published literature on the absorption
and distribution of either of the other inorganic phosphorus compounds was
that of Pena Payero et al. (1985). In that study an intense taste of matches
was experienced by a patient several minutes after a patch test of phosphorus
sesquisulfide was applied. Based on that finding, the authors suggested that
the chemical is rapidly absorbed through the skin.
Regardless of the route of absorption, some phosphine is excreted by the
lungs and may be recognized by its characteristic disagreeable odor (Hayes,
1982). This odor was noticed until the 11th day in the breath of a man who
swallowed aluminum phosphide tablets (Zipf et al., 1967), indicating that the
chemical may remain in the body for an extended period of time. Information
29
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on the elimination of the other inorganic phosphorus compounds was not
found.
3.2
BIOCHEMICAL EFFECTS
3.2.1 Elemental Phosphorus
Because white phosphorus intoxication produces a characteristic lesion,
fatty degeneration of the liver, several studies have been conducted to analyze
various biochemical changes;that may contribute to this effect. Seakins and
Robinson (1964) observed the following changes 24 hours after oral
administration of 1.5 mg of white phosphorus to rats: increased liver weight,
increased total amount and concentration of esterified fatty acids and choles-
terol, elevated total amount of phospholipids but decreased concentration, and
marked reduction of mean plasma concentrations of esterified fatty acids,
cholesterol, and phospholipids.
A small increase in hepatic triglycerides was observed in rats as early as
2 hours following administration of 10 mg/kg of white phosphorus by gastric
intubation. After 12 hours, hepatic triglycerides were significantly elevated.
Administration of the antioxidants glutathione or propyl gallate prior to white
phosphorus treatment prevented the elevation of hepatic triglycerides induced
by oral doses of phosphorus, indicating that antioxidants may prevent
phosphorus-induced fatty degeneration of the liver (Pani et al., 1972).
Jacqueson et al. (1979) demonstrated that total hepatic lipids and
triglycerides were elevated in rats after subcutaneous administration of 10
mg/kg of white phosphorus. Chromatographic analysis of hepatic trigly-
cerides showed increases in the relative amounts of oleic, palmitoleic, and
stearic acids, and a decrease in linoleic acid.
Ghoshal et al. (1969) showed that hepatic triglycerides in rats were
significantly elevated 6, 12, and 24 hours after administering 7.5 mg/kg of
yellow (white) phosphorus by gastric intubation. According to Ghoshal et al.
(1969, 1972), an observed increase in lipid peroxidation of hepatic
microsomes (measured by absorption of conjugated dienes), which precedes
the elevation in hepatic triglycerides, may be the cause of abnormal fat
accumulation in the liver of rats treated orally with 7.5 mg/kg of phosphorus.
In contrast, Pani et al. (1972) failed to find an increase in lipid peroxidation
(conjugated dienes) in rats given 10 mg/kg of white phosphorus orally.
The secretion of enzymes from hepatocytes, as reflected by their
increased appearance in the blood, serves as an indicator of hepatotoxicity
(Kulkarni and Hodgson, 1980). Plasma levels of glutamic-oxalacetic
transaminase (GOT) were significantly elevated 24 hours after administering
7.5 mg/kg of yellow (white) phosphorus to rats by gastric intubation; the levels
of glutamic-pyruvic transaminase (GPT) were not altered (Ghoshal et al.,
1969). Serum GPT levels in mice also remained unaltered one and four days
after administering 5 mg/kg of white phosphorus by gastric intubation (Hurwitz,
1972).
Pulmonary free cells collected by lavage from rats exposed by inhalation
to combustion products of red phosphorus/butyl rubber aerosols displayed
increased ATP levels and decreased ectoenzyme activity for 5'-nucleotidase
in alveolar macrophages (Aranyi et al., 1988). These biochemical alterations
were observed following single (1 g/m3 for 3.5 hours) or multiple exposures
(0.3 to 1.2 g/m3 for 2.25 hours/day, 4 consecutive days/week for 4 or 13
weeks), with the exception of a medium exposure level in the 13-week study.
Both changes were reversible.
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3.2.2 Inorganic Phosphorus Compounds
The mechanism of action of phosphine has been studied biochemically in
isolated mitochondria. Nakakita et al. (1971) showed that phosphine inhibits
the respiratory chain in rat liver mitochondria using succinate or pyruvate plus
malate as a substrate. Phosphine has a direct effect on electron transport in
mouse liver mitochondria and is thought to be a competitive inhibitor of
cytochrome oxidase (Chefurka et al., 1976). In vivo, acute inhalation exposure
of rats has been correlated with decreased mitochondrial respiration, affecting
particularly the oxidation of «-ketoglutarate. The coenzyme A levels in liver
mitochondria were slightly lower than in controls and the oxidative
phosphorylation of heart, but not of liver mitochondria, was reduced (Neubert
and Hoffmeister, 1960).
No information was found in the published literature on the biochemical
effects of phosphorus pentoxide, phosphoric acid, phosphorus trichloride,
phosphorus pentachloride, phosphorus oxychloride, or phosphorus sesqui-
sulfide.
3.3 Acute Toxicity
3.3.7 Elemental Phosphorus
A comprehensive study on the effects of white phosphorus smoke in rats
and guinea pigs was carried out by Brown et al. (1980). White phosphorus felt
cubes weighing 2.5 to 60 g were ignited in a chamber containing the test
animals. The major combustion component was phosphorus pentoxide in
addition to phosphorus trioxide and phosphorus dioxide. Rats were exposed
for 60 or 90 minutes to concentrations ranging from 505 to 2,018 mg/m3, with
concentration x time (CxT) values ranging from 30,300 to 181,620 mg-min/m3.
Guinea pigs were exposed for 5 to 60 minutes to concentrations ranging from
88 to 810 mg/m3, with CxT values ranging from 545 to 48,060 mg-min/m3.
Although occasional changes were observed in both species, concentration-
dependent or agent-related changes in the hematology and blood chemistry
were not observed.
In rats, the acute signs of toxfcity were gasping and ataxia at exposures of
797 mg/m3 for 90 minutes (71,753 mg-min/m3); nevertheless, the animals
recovered. Respiratory distress was observed in animals surviving higher
exposures, but they recovered within 24 hours. The mortality ranged from 0
percent at 505 to 797 mg/m3 to 90 percent at 2,018 mg/m3. An LCt5p of
94,126 mg-min/m3 was determined by statistical analysis of the concentration-
response data. Histopathological examination of selected animals from the
high exposure group showed fibrin thrombi in heart and lungs, acute diffuse
congestion, and focal perivascular edema and hemorrhage in the lungs. A
definite relationship between the induction of the lesions and exposure was not
established (Brown et al., 1980).
One guinea pig exposed to 176 mg/m3 died during the 30 minute
exposure period. However, no other deaths or adverse effects were observed
in guinea pigs at CxT values ranging from 545 to 3,840 mg-min/m3.
Respiratory distress was a common problem in animals exposed to CxT
values higher than 5,410 mg-min/m3. Almost all the animals that survived the
immediate effects of exposure subsequently recovered. All animals exposed
to CxT values of 14,310 and 48,060 mg-min/m3 corresponding to 477 mg/m3
for 30 minutes and 801 mg/m3 for 60 minutes, respectively, died during
exposure or within 15 minutes after exposure, except one animal which
31
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survived for 3 days. An LCt50 of 5,321 mg-min/m3 was established from the
concentration-response data. Studies on pulmonary resistance in guinea pigs
exposed to 3,840 and 5,280 mg-min/m3 did not reveal a significant difference
between exposed and control animals (Brown et al., 1980).
In a series of tests, White and Armstrong (1935) exposed mice, rats, and
goats to white phosphorus for 1 hour at levels ranging from 110 to 1,690, 380
to 4,810, and 540 to 11,470 mg/ms, respectively. Mortality ranged from 5
percent at 110 mg/m3 to 95 percent at 1,690 mg/m3 in mice. Rats appeared
to be much more tolerant of the phosphorus smoke than mice. The mortality
ranged from 0 at 380 mg/m3 to 100 percent at 4,810 mg/m3. In goats,
mortality ranged from 0 at up to 4,810 mg/m3 to 100 percent at 8,010 mg/m3.
Signs of toxicity were noted in exposed animals at the lowest exposure levels.
The toxic manifestations included pulmonary congestion and hemorrhage and
cloudy swelling of the liver and kidneys. Cloudy swelling of the heart was also
noted in mice and rats. In goats, inflammatory reactions in the trachea with
pus and pneumonia were noted. Deaths were attributed to the toxic effects of
the phosphorus in rats, the irritative and toxic effects of the phosphorus in
goats, and the irritative effects of the phosphorus in mice.
Death occurred within four days in eight dogs given oral doses of 0.5 to
1.0 mg/day of phosphorus (Williamson and Mann, 1923). Three animals
developed severe hypoglycemia, which became apparent only a few hours
prior to death. The blood sugar level was normal in the remaining animals.
Blood urea was increased in seven animals, significantly in six. The severe
hypoglycemia suggested that the liver was damaged.
Cutler (1931) obtained similar results with respect to the induction of
hypoglycemia. Dogs were administered phosphorus orally in doses of 2 mg/kg
on day 1, 1 mg/kg on day 3, and 1 mg/kg on day 5, but only if intoxication was
not observed earlier. Overt symptoms of phosphorus poisoning included
sluggishness, tremors, vomiting, convulsions, and coma. There was a
decrease in blood sugar in all animals in addition to increases in guanidine,
nonprotein nitrogen, amino nitrogen, urea, and creatine.
Lee et al. (1975) administered a 0.1 percent solution of white phosphorus
by gastric intubation to rats, mice, and rabbits. Animals surviving treatment
were observed daily for mortality and signs of toxicity. Both mice and rats
suffered from depression and anorexia. The livers were enlarged and
yellowish in color.
Brown et al. (1980) administered to rats 1.48, 1.86, 2,43, or 2.96 g/kg of
white phosphorus/felt smoke condensate by gastric intubation. The acute
signs of toxicity were lethargy, gastric distress, and prostration. Death
occurred within 24 hours.
O'Donoghue (1985) reported that acute poisoning following large doses of
yellow phosphorus results in fatty degeneration in the parenchymal cells of
major organs, especially the liver, kidneys, and heart. Neurological effects
included vascular endothelial damage, hemorrhage, and enlargement or
swelling of the glia. Diffuse cortical and focal perivascular neuron
degeneration may also occur.
Urine, blood, and liver of rabbits injected subcutaneously with 5 mg/kg of
yellow (white) phosphorus were subjected to chemical analysis, and liver and
kidney specimens were analyzed microscopically (Huruya, 1928). Fatty
deposits appeared in the interstitium and parenchyma of the liver. Damage to
the kidney was found in the renal tubules but rarely in the glomeruli. Liver
weight, nonprotein nitrogen, polypeptide nitrogen, total fatty acid, and
cholesterol increased with severity of fatty degeneration of the liver. Chemical
analysis of blood revealed that total nitrogen, nonprotein nitrogen, and
32
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polypeptide nitrogen also increased. The volume of urine and the urine
absolute total nitrogen and percentage urea nitrogen decreased, whereas the
alkalinity and ammonia nitrogen increased.
Buchanan et al. (1954) injected three dogs subcutaneously with 0.4 and
one dog with 0.2 mg/kg/day of phosphorus. Two of three animals given 0.4
mg/kg/day died on day 6, and the third animal stopped eating on day 7 and
was killed on day 14. On day 3 the dogs began to vomit mucous material
which became bloody prior to death. All organs were hemorrhagic; fatty
degeneration of the liver was observed in a narrow zone around the central
vein. The kidney tubules were necrotic and fatty degeneration was observed
in those less severely damaged. The one dog given 0.2 mg/kg/day had
hemorrhagic liver, intestines, and kidneys. Fatty vacuolization was observed
in the peripheral areas of the lobules in the liver. Kidney tubules had granular
plugs and the epithelium began to slough off. Clinical studies showed a
significant increase in urine creatine and a decrease in creatinine levels
indicating an impairment in kidney function. In addition, urine choline levels
showed a slight increase immediately preceding death.
Experimental white phosphorus burns produced in New Zealand white
rabbits caused postburn electrolyte changes consisting of depression of
serum calcium and elevation of serum phosphorus. In addition,
electrocardiographic abnormalities (prolongation of the QT interval,
bradycardia, and ST-T wave changes) were observed. Mortality rates were 65
to 85 percent (Bowen et al., 1971).
Appelbaum et al. (1975) evaluated the subcellular changes resulting from
experimental phosphorus burns in rats. Pathological changes were observed
72 hours postburn, primarily in the kidneys. The changes included ischemic
glomeruli, capillary collapse, proliferation of mesangial areas, basement
membrane thickening, and necrosis in proximal tubules. Effects included
oliguria, polyuria, and anuria. Serum urea, serum glutamic pyruvate
transaminase (SGPT), and phosphate were elevated.
Marrs (1984) exposed rats and rabbits for 30 minutes to single exposures
of smoke from two pyrotechnic mixtures. Composition I contained 95 percent
red phosphorus and 5 percent butyl rubber (0.68 g/m3 as phosphorus) and
composition II contained 97 percent phosphorus and 3 percent butadiene
styrene (0.67 g/m3 as phosphorus). Both mixtures produced histological
changes in the respiratory tract that included abnormalities of the larynx and
trachea, and alveolitis; a few cases of bronchopneumonia were observed.
Rats exposed to red phosphorus/butyl rubber aerosols at concentrations
ranging from 0.5 to 3 g/m3 for 1 to 4 hours showed highly significant
decreases in pulmonary bactericidal activity to inhaled radiolabelled Klebsiella
pneumonias after single or multiple exposures. Pulmonary free cells obtained
by tracheobronchial lavage from rats exposed to the higher concentrations
were significantly decreased (Aranyi, 1983). In a later experiment Aranyi et al.
(1988) exposed rats to combustion products of red phosphorus/butyl rubber
aerosols at a concentration of 1 g/m3 for a 3.5 hour single exposure. Exposed
rats showed a decreased ability to kill inhaled Klebsiella. As in the earlier
study, pulmonary free cells collected by lavage were decreased.
Subsequent mortality studies with red phosphorus/butyl rubber aerosols
suggest that exposure concentration is the determining factor in mortality
rather than length of exposure. Rats were given single 1-hour exposures of
2.0, 2.22, 2.62, 3.09, or 3.15 g/m3 and observed for 14 days. Maximum
mortality (20 to 25 percent) occurred after a 1 -hour exposure to 3 g/m3, while
2.62 g/m3 resulted in 6 percent deaths. A single 4-hour exposure to 0.88 g/m3
33
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with a CxT value similar to those in the 3.09 to 3.15 g/m3 1-hour exposures
was not fatal (Aranyi, 1983).
In a range-finding study, Burton et al. (1982) exposed rats to 3.1, 4.3, 5.3,
or 8.5 g/m3 red phosphorus/butyl rubber smoke aerosols for 1 hour or to 1.5
g/m3 for 4 hours. Chemical analysis of the aerosols suggested that the
principal product of red phosphorus/butyl rubber combustion is phosphorus
pentoxide, which then hydrolyzes to form a series of polyphosphoric and
cyclopolyphosphoric acids. Also detected were low concentrations of
phosphine. Lesions common to all exposed groups involved the larynx and
epiglottis. Pulmonary congestion, edema, and hemorrhage were pronounced
only in the two highest exposure groups. Deaths occurred on days 1 through
11 postexposure, suggesting both acute and delayed effects. Of the 10
animals exposed to 3.1 g/m3 for 1 hour, one animal died on day 6 and 10
postexposure. Exposure to 1.5 g/m3 for 4 hours resulted in 4 deaths.
Weimer et al. (1977) exposed rats, guinea pigs, and dogs to red
phosphorus/butyl rubber screening smoke. Airborne concentrations were
based on phosphoric acid content. Rats were exposed to from concentrations
1,128 to 1,882 mg/m3 for 60 to 240 minutes; guinea pigs from 120 to 2,277
mg/m3 for 5 to 150 minutes; and dogs from 1,212 to 1,882 mg/m3 for 30 to
240 minutes. Based on mortality data, red phosphorus/butyl rubber smoke
appeared to be only slightly toxic in rats and dogs but highly toxic in guinea
pigs. The mortality in rats ranged from 0 percent at 1,128 mg/m3 for 60
minutes to 100 percent at 1,882 mg/m3 for 240 minutes. In guinea pigs, the
mortality ranged from 0 percent at 120 mg/m3 for 5 minutes to 100 percent at
1,483 mg/m3. All but one of the dogs survived the smoke exposures.
Following exposure, all animals showed signs of respiratory distress that was
more marked with increasing exposure levels and time. Animals usually
displayed hyperactivity which persisted up to 2 days postexposure.
Conjunctivitis was noted in rats and dogs at the higher exposure levels.
Exposed male rats had significantly lower liver weights than control animals.
Kidney and body weights were also less than those in controls at the higher
exposure levels.
3.3.2 Inorganic Phosphorus Compounds
Symptoms observed in rats, resulting from single acute inhalation expo
sures to phosphine, were typical of mild irritation, such as red ears, sali-
vation, lacrimation, face pawing, and dyspnea. Histologic examination of
tissues did not show any pathologic changes. The 4-hour LC50 was 15.4
mg/m3. Repeated 4-hour inhalation exposures to about 5.6 mg/m3 for 10 days
produced mild respiratory irrjtation and in addition a slightly reduced body
weight gain, which returned to normal after 12 days. Piloerection was noted
during the fourth and subsequent exposures (Waritz and Brown, 1975).
Little species variation was observed in rats, rabbits, guinea pigs, and cats
exposed by inhalation to phosphine at concentrations ranging from 7.5 to
564.0 mg/m3 (Klimmer, 1969). At high phosphine concentrations, the animals
quickly developed lassitude, immobility, restlessness, ataxia, pallor, convul-
sions, and death within 30 minutes or less, with apnea preceding cardiac
arrest. Similar symptoms with slower onset and progression were noted at the
intermediate concentrations. The first several 6-hour exposures to the lowest
fatal concentration (7.5 mg/m3) did not produce detectable adverse effects;
however, further exposure led to pulmonary edema and respiratory failure.
Exposure-response studies in rats indicated that at concentrations of 7.5
mg/m3 phosphine and above, the effects were cumulative, while concentra-
34
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tions of 3.75 mg/m3 and below produced no clinical evidence of cumulative
effects (rats tolerated 3.75 mg/m3 for 820 hours without clinical injury)
(Klimmer, 1969).
The only pathological change in rats, rabbits, guinea pigs, and cats killed
rapidly by high exposures to phosphine may be pulmonary edema. Those
killed more slowly may show pulmonary edema, hemorrhages of the mucosa,
slight diffuse fatty infiltration of the liver, and isolated necrosis of the tubular
epithelium of the kidneys. Pathological changes in the brain may include
pronounced dilatation of the perivascular spaces, changes in the nuclei of
ganglion cells with glial reaction, disintegrating Purkinje cells with
multiplication of the Bergmann glia, edema of the white matter of the
cerebellum, and occasional damage to the capillary epithelium. The glial
reactions were not found in cats and guinea pigs (Klimmer, 1969). Table 3-2
summarizes some lethality data in laboratory animals due to phosphine
inhalation.
Acute toxicity data for phosphorus pentoxide in laboratory animals indi
cate a wide interspecies difference. The acute 1-hour inhalation toxicity of
phosphorus pentoxide in terms of LC50 values is 61, 271, 1,212, and 1,689
mg/m3 for guinea pigs, mice, rats, and rabbits, respectively (Ballantyne, 1981).
The only information regarding the acute toxicity in laboratory animals
was an oral LD50 value of 1,530 mg/kg for rats and a dermal LD50 value of
2,740 mg/kg for rabbits (RTECS, 1989).
A slight transient epithelial edema and conjunctival hyperemia was noted
in a rabbit's eye irrigated for 5 minutes with a 0.16 M solution of ortho-
phosphoric acid (H3PO4) buffered to pH 3.4. The eye was normal by the next
day. However, injection into the rabbit corneal stroma or application of
metaphosphoric acid (HPO3) to the cornea after removal of the epithelium,
caused detectable injury below pH 5.5 (Grant, 1974).
Grant (1974), citing Flury and Zernik (1931), report that cats exposed to
phosphorus trichloride concentrations of 11 to 23 mg/m3 for 6 hours
developed respiratory difficulties and conjunctivitis; exposure to 130 to 510
mg/m3 for the same time period caused clouding of corneas and severe
systemic effects.
Weeks et al. (1964) studied the acute vapor toxicity from single 4-hour
exposures of rodents to the vapors of phosphorus trichloride and the effects
on its toxicity when the vapor was neutralized with ammonia in air. The 4-hour
LC50 for phosphorus trichloride in rats and guinea pigs was 590 mg/m3 and
283 mg/m3, respectively. During exposure to phosphorus trichloride, rats and
guinea pigs were restless and agitated and exhibited porphyrin secretion
Table 3-2. Lethality of Phosphine in Animals
Species Route Concentration/Effect
Rat
Mouse
Guinea pig
Rabbit
Cat
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
16.5 mg/m3 4 hr, LCSO
412.5 mg/m3 2 hr, LC LO
I50.0mg/m32hr, LCLO
3,750.0 mg/m3 20 min, LCLO
75.0 mg/m3 2 hr, LCLO
Source: RTECS 1989
35
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around the eyes and reddish-brown discoloration of the pelt. The chemical
was severely corrosive, producing necrosis of paws and nostrils. Areas of
necrosis appeared in kidney tubules; pulmonary damage was only slight.
When ammonia was added to the atmosphere, the symptoms of irritation were
markedly reduced. The toxicity of phosphorus trichloride (which hydrolyzed
about 40 percent) was jimly slightly reduced in rats, but significantly reduced
in guinea pigs.
Russian investigators (Roshchin and Molodkina, 1977) carried out acute
toxicity studies with phosphorus trichloride in rats, guinea pigs, mice, and
rabbits. Acute inhalation as well as oral administration by gavage produced
pronounced irritation and systemic effects in all species tested. The irritating
effects, characterized by corneal turbidity, skin ulcers around mouth and nose,
and respiratory irritation, were attributed to the hydrolysis of phosphorus
trichloride to hydrochloric and phosphoric acid. Dystrophic changes were
found in kidneys, liver, and nervous system. Roshchin and Molodkina (1977)
classified the chemical as extremely toxic when inhaled (LC50 = 226 mg/m3
or about 40 ppm) and less toxic by the oral route (LD50 = 550 mg/kg).
Acute exposure of laboratory animals by inhalation or gastric intubation to
phosphorus pentachloride (levels not reported) produced respiratory irrita-
tion, and dystrophy in the kidneys, liver, and nervous system (Roshchin and
Molodkina, 1977). The irritant effects were less severe than those observed
with exposure to phosphorus trichloride. The compound was less toxic when
taken orally than by inhalation. The inhalation LC50 for rats is 295 mg/m3. The
oral LD50 is 660 mg/kg (Sax, 1984).
Weeks et al. (1964) studied the acute inhalation toxicity of phosphorus
oxychloride in rats and guinea pigs. During exposure to the chemical, the
animals showed signs of irritation and developed porphyrin secretions around
the eyes. The 4-hour LC50 values were 303 mg/m3 and 335 mg/m3 for rats
and guinea pigs, respectively. All deaths occurred within 48 hours of exposure,
preceded by gasping and convulsions. In surviving animals, the toxic
symptoms abated during the 14-day observation period. The lungs of animals
that died were dark red. Tissue examination showed desquamation of tracheal
and bronchial epithelium, resulting in plugging of the lumen of the bronchi and
bronchioles. The toxicity of phosphorus oxychloride, which hydrolyzed about
15 percent in the vapor phase, was not significantly affected by neutralization
with ammonia.
Roshchin and Molodkina (1977) carried out acute, subacute, and chronic
toxicity studies of phosphorus oxychloride on specified numbers of rats,
guinea pigs, mice, and rabbits. However, in describing the effects, the number
and species tested generally were not specified, except for a few instances
which mentioned rats. Acute effects of phosphorus oxychloride resulting from
a single inhalation or oral exposure were respiratory tract irritation and
dystrophic changes in internal organs, particularly in kidneys, liver, and
nervous system. The inhalation LC50 was 71 mg/m3 (exposure time not given).
An oral LDLO value of 100 mg/kg in dogs was the only information found
for effects of phosphorus sesquisulfide in experimentla animals (Sax, 1984).
3.4 SUBCHRONIC AND CHRONIC TOXICITY
3.4.1 Elemental Phosphorus
Inuzuka (1956) reported that rats exposed to 150 to 160 mg/m3 yellow
phosphorus 30 minutes/day for 60 days developed bone changes consisting
36
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of a widened epiphyseal line, irregular cell configuration, trabeculation with
insufficient ossification, and developmental changes of long bones. Young
animals were more severely affected than older ones. There were, however,
no significant changes in the Ca/P ratio or phosphorus content of long bones.
Brown et al. (1981) carried out a systematic study to examine the effects
of subchronic exposure to white phosphorus smoke on rats. The four
concentrations were 1,161 mg/m3 (high), 589 mg/m3 (intermediate), 193
mg/m3 (low), and 0 (control). The animals were exposed to smoke, generated
by burning white phosphorus/felt, for 15 minutes/day, 5 days/week for 13
weeks. The mortality rate was high in the high-exposed group, but no animals
in the intermediate and low exposure groups died prior to scheduled sacrifice.
Of the 72 rats exposed to the highest concentration of phosphorus, 23 died
within 6 weeks, and by the end of the experiment, a total of 29 had died.
Immediate effects of the high levels of phosphorus were dyspnea and
wheezing, which cleared up within 2 hours.
There were no agent-related changes in body and organ weights during
the course of this experiment. Blood chemistry and hematology as well
showed no agent-related changes, suggesting that inhalation of white
phosphorus/felt smoke does not produce systemic effects under the
conditions of this study. Pulmonary rales were noted in 3 of 12 rats exposed to
the high level of phosphorus, but did not occur in the intermediate, low, or
control groups. There were also indications that the tidal volume was reduced
and breathing rate was increased in males in the high exposure group for the
duration of the study (Brown et al., 1981).
Histopathological evaluations showed that > 70 percent of the animals that
died spontaneously after exposure to the white phosphorus smoke developed
laryngitis, tracheitis, and congestion. Bronchitis was observed in 20 percent
and interstitial pneumonia in 53 percent. With the exception of interstitial
pneumonia, these lesions were agent-related. Laryngitis was moderate in the
high-exposure group; tracheitis was moderate to slight in the high-exposure
group and slight to minimal in the intermediate-exposure group. No cases of
laryngitis and only one case of tracheitis were observed in the low-exposure
group; congestion and bronchitis were absent. Under the conditions of this
study, the lowest-observed-adverse-effect level (LOAEL) was 193 mg/m3
{Brown'et al., 1981).
A recent Russian study investigated the morphology of the oral mucosa in
rats after long-term exposure to the atmosphere of a phosphorus factory
(Ruzuddinov and Rys-Uly, 1986). Rats were kept in the furnace room of a
phosphorus factory 4 hours daily, 5 days/week for up to 4 months (exposure
levels not given). After 1 month, the structural integrity of the epithelium of the
oral mucosa was normal in most animals. In the second month, hyperkeratosis
of the mucosa of the gum, cheek, hard palate, and tongue and vascular
disturbances in the form of increased permeability of the capillary walls were
observed. Progressive pathological changes were found in the third and fourth
month of exposure. Toward the end of the experiment, dystrophic and atrophic
changes were observed in the epithelium, leading in some cases to a
decrease in thickness of the epithelial layer. The maximum allowable level in
the Soviet Union is 0.03 mg/m3 (International Labour Office, 1980).
Strelyukhina (1984) reported hepatic changes in rats in the form of
congestion, fatty degeneration of the hepatocytes, and toxic hepatitis after
orally ingesting 1.0 mg/kg of white phosphorus for 15 days to 4 months.
Fibrosis and internodular cirrhosis was evident in some animals exposed to
phosphorus for 3 to 4 months. Similar results were reported by Mallory (1933)
37
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after orally administering rabbits and guinea pigs 0.25 to 1.0 mg/kg
phosphorus/day until the animals were sacrificed.
Phosphorus-induced cirrhosis of the liver was observed at 8 weeks in
animals administered 1 mg/kg, while animals given lower doses required over
4 months to develop cirrhosis of the liver. Phosphorus caused damage to
fibroblasts of the stroma and to hepatic cells throughout the liver. Damage to
fibroblasts was followed by regeneration as evidenced by mitotic activity and
periportal fibrosis which extended irregularly into the lobule. Damage to
hepatic cells, which was extensive after administering 1 mg/kg/day, was also
followed by regeneration.
Ashburn et al. (1948) were not able to induce clear-cut cirrhosis in guinea
pigs administered phosphorus for 35 weeks. However, other extensive liver
changes were observed. The animals were given 0.75 mg/kg for 4 days each
week or 1.5 mg/kg twice weekly in a 0.1 percent solution of olive oil, per os.
The lesions appearing after dosing 4 times per week were identical in
incidence and type to those appearing after dosing twice weekly. Nine weeks
after initiating treatment, hepatic lesions appeared in the hilar portion of most
lobes and extended toward the surface of the liver. As treatment progressed,
the lesions increased in size and frequency. Extreme atrophy was observed in
lobes containing lesions, whereas hypertrophy was observed in uninvolved
lobes. Early lesions were characterized by destruction of parenchyma cells
and hydropic, fatty, or other degenerative changes in surviving cells. Other
changes included bile duct proliferation and an inflammatory response with
infiltration of lymphocytes and large mononuclear cells. In late lesions, few
parenchyma cells, fibrous tissue, a few normal bile ducts, and collapsed
sinusoids were observed. Necrosis was limited to a few isolated cells
distributed throughout the liver. A slight increase in the amount of periportal
collagen was observed after 16 weeks.
Sollmann (1925) found that rats maintained on a diet containing
phosphorus experience weight loss. Young female rats were placed on a diet,
containing phosphorus at daily doses of 0.072 mg/kg, 0.018 mg/kg, or 0.0033
mg/kg for 22 weeks. A pronounced depression of growth and weight loss was
observed in rats administered 0.072 mg/day. Animals removed from the diet at
10 weeks did not gain but ceased to lose weight. Similar, but less severe
effects were noted in animals exposed to 0.018 mg/kg. Removal from the diet
containing phosphorus at 16 weeks caused normal growth to resume. Growth
of rats placed on 0.0033 mg/kg was unaffected by phosphorus up to the 15th
week, at which time growth ceased. Removal from the diet caused a rapid
increase in weight gain such that at 22 weeks treated animals weighed more
than controls. Older male rats on a dose regimen of 0.0027 mg/kg/day of
phosphorus for 25 weeks showed considerable fluctuations in growth prior to
the 15th week. Thereafter growth was rapid and was 13 percent that of
controls by the 25th week of treatment. A recent study by Monsanto (1985)
did not confirm the extreme weight loss in rats given 0.075 mg/kg/day of white
phosphorus prior to and through two gestation periods.
Adams and Sarnat (1940) reported that phosphorus has an effect on
bones. These researchers administered 0.6 mg/day of yellow phosphorus
orally to rabbits for 13 to 117 days and phosphorized cod liver oil (0.01
percent phosphorus) to rats for 22 to 57 days. General growth and longitudinal
bone growth in both rabbits and rats were adversely affected by yellow
phosphorus. The average daily increase in tibial diaphysis was 0.36 mm in
control rabbits and only 0.27 mm in phosphorus-treated litter mates.
Histological evaluation showed dense "phosphorus" bands in the metaphysis
of long bones during the period of exposure and increased numbers of
38
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trabeculae due to reduced resorption of the intercellular calcified cartilage
matrix. Zones of abnormally calcified dentin were also found in molars and
incisors during the period of ingestion. Thickening and increased radiographic
density of the metaphyseal bone were observed by Whalen et al. (1973) after
feeding rats a diet containing approximately 0.065 mg phosphorus/kg/day for
16 days. Histologically, the trabeculae were found to be abnormally thickened,
accounting for the increased density.
Fleming et al. (1942) administered white phosphorus mixed with stock diet
at equivalent doses of 0.2 to 1.6 mg/kg/day to rats for their entire lifetime, (up
to 512 days in some animals). Except for the group receiving 0.8 mg/kg/day,
mortality decreased with decreasing dosage; the average survival of all treated
animals, however, was greater than or equal to that of controls (Table 3-3).
Histopathological evaluation revealed changes in the bones consisting of
thickening of the epiphyseal line and extension of the trabeculae into the shaft
in all phosphorus exposed animals.
As part of the same experiment Fleming et al. (1942) also administered
white phosphorus to rats and guinea pigs by subcutaneous injection. Rats
were injected twice weekly with doses ranging from 0.05 to 3.2 mg/kg/day up
to 720 days and guinea pigs with doses ranging from 0.05 to 0.4 mg/kg/day up
to 1,160 days. The mortality rate in treated rats decreased with decreasing
doses of phosphorus (Table 3-3). At the lowest doses (0.05 or 0.1 mg/kg/day),
the mortality rate was lower than that in controls. Thus, as in the oral study,
low doses of phosphorus were associated with improved survival in rats.
Almost all the rats exposed to phosphorus at all dose levels developed bone
changes consisting of thickening of the epiphyseal line and extension of
trabeculae into the shaft. These changes were more pronounced than those
observed in rats administered phosphorus in their diets. The livers of a few
animals showed mild fatty degeneration and those of two animals, periportal
fibrosis. Liver damage, therefore, was insignificant considering the long period
of treatment. Guinea pigs, given twice weekly subcutaneous injections of
phosphorus, showed similar skeletal changes, though less severe than those
observed in rats. The relationship between bone pathology in laboratory
animals and the effects of chronic occupational exposure to elemental
phosphorus in humans (see Section 3.8.1, necrosis of the jaw bone) is
unknown.
One-year-old dogs weighing 10 kg were injected subcutaneously with 0.1
mg/kg/day of phosphorus for 55 to 115 days (Buchanan et al., 1954). All
animals lost 2.5 to 3.0 kg of weight between day 25 and 51 of treatment, then
gained 1.85 to 2.85 kg prior to sacrifice. All animals became ill prior to
sacrifice. Some dogs developed fatty degeneration of the liver, hydropic
degeneration of the kidney, and accumulated large amounts of hemosiderin in
the spleen.
Because phosphorus causes changes indicating that fat metabolism may
be disturbed, such as fatty degeneration of liver and other organs, Fleming
and Collings (1951) carried out studies to determine if the fat content in the
blood as measured by the chylomicron count, may also be altered by
phosphorus. Rats received 1.1 mg/kg/day of yellow (white) phosphorus three
times a week by subcutaneous injection for 45 days. Throughout the
experiment, there was a slightly elevated base count in phosphorus treated
animals. The chylomicron count of control animals peaked at 4 hours, while
the 4-hour chylomicron counts of treated animals were markedly reduced until
the 12th day. Thereafter, they increased until near normal values were
reached by the end of the experiment.
39
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Table 3-3
Dose
(mg/kg/day)
Oral and Subcutaneous Toxicity of White Phosphorus
in Rats
Total Dose
(mg)
Average Survival
(days)
Deaths/100
Animal-Days
Oral
1.6
0.8
0.4
0.2
Controls
718
265
181
96
0
449
332
454
479
348
0.25
0.30
0.22
0.21
0.33
Subcutaneous
3.2
1.6
1.2
0.8
0.4
0.2
0.1
0.05
Controls
10
15
13
112
136
89
53
31
0
3.2
0.3
11
140
340
442
530
610
480
31.6
10.7
9.1
0.72
0.30
0.23
0.19
0.17
0.24
Source: Fleming et al. (1942).
Lhota and Hannon (1979) observed that rats injected subcutaneously with
0.5,1.0, or 2.0 mg/kg/day of yellow (white) phosphorus for 30 days or less lost
weight. Young adult rats injected with 0.5 mg/kg/day lost less weight than fully
mature or young rapidly growing rats. Whatever the age or weight at the
beginning of treatment, the period of weight loss was followed by a period of
cyclic weight loss and gain with an overall net weight gain. Exposure to 1.0 or
2.0 mg/kg led to a dose-dependent progressive weight loss and eventual
death in young rapidly growing rats.
In the only study found evaluating the effects of subchronic exposure to
red phosphorous in experimental animals, Aranyi et al. (1988) exposed rats to
combustion products of red phosphorus/butyl rubber aerosols at
concentrations ranging from 0.3 to 1.2 g/m3 for 2.25 hours/day, 4 consecutive
days/week for 4 and 13 weeks. Exposed rats showed a decreased ability to kill
inhaled Klebsiella. Pulmonary free cells collected by lavage were decreased.
Concentrations of 0.75 g/m3 or more produced terminal bronchiolar fibrosis in
all rats after the 4- and 13-week exposures. The severity of the lesions
increased with increasing concentrations and duration of exposure.
40
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3.4.2 Inorganic Phosphorus Compounds
Several studies on the effects of long-term exposure of laboratory animals
to phosphine have been identified in the published literature; however, these
studies mainly address the health effects associated with the ingestion of
phosphine-treated food or feed items. The only other study found which
addresses the effects associated with long-term exposure to the inorganic
phosphorus compounds addresses the effects of inhaled phosphorus
oxychloride. The effects of long-term exposure to phosphorus pentoxide,
phosphoric acid, phosphorus pentachloride, phosphorus chloride, and
phosphorus sesquisulfide in laboratory animals are unknown.
Mueller (1940) found that rabbits tolerated phosphine concentrations of 7
mg/m3, 4 hours/day, for 2 months, but died after seven similar exposures to 14
mg/m3. After repeated exposures to 14 mg/mS, some of the animals still
appeared well, but experienced breathing difficulty and paralysis shortly
before death. A -concentration of 35 mg/m3 was fatal after a few hours.
Histologic examination of tissues revealed a pronounced hyperemia in all
organs, particularly in lungs, liver, kidneys, and brain. Other pathologic
changes included heart enlargement, lung edema, and mucous accumulation
in trachea and bronchi. The author indicated that the toxic effects may be
cumulative. »
Several investigators addressed the potential health hazards associated
with the consumption of phosphine-fumigated foods. Kadkol and Jayaraj
(1968) showed that ingestion of a phosphine-fumigated rice diet by rats for 12
weeks did not modify weight gain or food intake, nor was there a change in
hemoglobin levels or histopathology. Determination of liver and kidney weights
showed a slight exposure-related increase in male rats. The authors did not
indicate the levels of residual phosphine in the treated diet. (McGregor, 1980).
Hackenberg (1972) fed rats for two years a diet treated with high concen-
trations of phosphine-releasing Phostoxin® tablets, using an equivalent of 10
times the recommended concentration of Phostoxin® The average residual
phosphine level in 3 of 16 batches of treated diet was 0.996 mg/kg. Behavior,
general appearance,- survival, body weight, food consumption, hematology,
blood chemistry, urinalysis, and bone smear data, as well as microscopic
findings and tumor analysis did not reveal any toxic effects from consumption
of the Phostoxin®-treated diet.
A recent study also indicated that long-term ingestion of a phosphine-
fumigated feed does not produces adverse health effects in rats. Cabrol Telle
et al. (1985) exposed rats to about 0.005 mg/kg (5 ppb) of phosphine in the
diet for two years. There were no marked changes in growth, food intake,
nitrogen balance, functional behavior, or incidence or type of tumor.
Subchronic exposure of rats to 1.34 mg/m3 (0.2 ppm) of phosphorus
oxychloride affected body weight gain and caused changes in respiration rate
and oxygen consumption. Urinary hippuric acid excretion was decreased,
indicating a disturbance in the detoxifying function of the liver. After an
exposure of four months, the experimental animals exhibited pronounced
morphological changes of the respiratory system, characterized by catarrhal
desquamative rhinitis, tracheitis, and bronchitis. Other pathological changes
were degenerative changes of the brain and mild liver and kidney distrophy.
The animals showed signs of enterocolitis. Changes were also noted in
calcium, phosphorus, and chlorine metabolism. Changes in bone tissue were
indicative of osteoporosis (Roshchin and Molodkina, 1977).
41
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3.5 TERATOGENICITY AND REPRODUCTIVE EFFECTS
3.5.1 Elemental Phosphorus
Starke et al. (1982) reported the effects of exposure to airborne white
phosphorus/felt smoke on development and reproduction in rats. Pregnant
rats were exposed daily for 15 minutes (starting on day 6 of pregnancy and
continuing to day 15) to concentrations of 0, 500, or 1,000 mg/mS
phosphorus/felt smoke. The results are shown in Table 3-4. Major variations
were unilateral anophthalmia, narrow atria, short tongue, brachygnathia, and
thin-walled heart. Minor variations were ectopic kidneys, ectopic testicles, and
reversed ductus arteriosus. This study suggested the possibility of
developmental toxicity from inhalation of white phosphorus/felt smoke.
As part of the same investigation (Starke et al., 1982), male rats were
exposed for 15 minutes/day, 5 days/week for 10 weeks and female rats were
exposed similarly for 3 weeks to 0, 500, or 1,000 mg/m3 white phosphorus/felt
smoke to evaluate the effect of varying concentrations of phosphorus on the
reproductive potential of these animals. Exposure of the females continued
through mating, gestation, and lactation. Litters were exposed for up to 21
days of age. There were no gross abnormalities in any of the pups delivered
nor significant differences in the litter sizes. The mean body weights of the
pups in the high-exposure group were lower at all ages than those in the low-
exposure and control groups. The survival, viability, and lactation indices of
pups in the highest exposed animals were significantly lower than the other
groups. Because the mothers did not resume nursing for 2 to 3 hours after
exposure, this difference was attributed to the weakened condition of the
mothers exposed to 1,000 mg/m3.
A high mortality rate in female rats exposed to phosphorus was observed
in a one-generation reproduction study conducted by Monsanto (1985). The
increased mortality was attributed to difficulty in parturition. Yellow (white)
phosphorus was administered by gavage at levels of 0.005, 0.015, or 0.075
mg/kg/day for 80 days prior to and through two gestation periods. Sixteen of
the thirty females in the high exposure group died during treatment, 13 of
which died during the last 2 days of gestation. The mortality rates were low in
the other exposure groups and in males. No other clinical signs of toxicity
were observed except for hair loss in the high-exposure group.
Histopathological evaluation, including that of bone and liver, did not reveal
significant effects of yellow phosphorus in exposed males, females, or pups.
A "nq-observed-adverse-effect level" (NOAEL) of 0.015 mg/kg/day was
established.
3.5.2 Inorganic Phosphorus Compounds
No information was found in the published literature on the teratogenicity
of reproductive effects of the inorganic phosphorus compounds.
3.6 Mutagenicity
3.6.1 Elemental Phosphorus
The mutagenicity of phosphorus has been evaluated in microbial, insecti-
cidal, and mammalian test systems. White and red phosphorus were tested
for mutagenicity in the Ames test. White phosphorus in water ("phossy
water") at a concentration of 100 yL/plate produced no mutagenic activity in
Salmonella typhimurium strains TA100, TA1535, TA98, TA1537, and TA1538
either in the presence or absence of metabolic activation (Ellis et al., 1978). A
42
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Table 3-4 White Phosphorus/Felt Smoke Induced Visceral and
Skeletal Variations and Abnormalities
Variations
and Abnormalities
Air Low Dose High Dose
Control 500 mg/m3 1,000 mg/m3
Visceral
Prominent renal pelvis 43 5
Ectopic kidney(s) 1 4
Narrow atrium 11 1
Thin-walled heart 1
Reversed ductus arterious "
Underdeveloped testicles 3 1
Ectopic testicles 3
Hemorrhagic eyes 1
Anophthalmia unilateral*
Short tongue* 1 1
Brachygnathia* 1
Skeletal
Fourteenth rib extra (rudimentary) 1 g 39 25
Cleft sternebrai 2 0 2
Dumbbell-shaped sternebrae 16 7 6
General hypoplasia of the 35 46 38
sternebrae
Dumbbell-shaped vertebrae-thoracic 9 11 2
Hypoplasia of xyphoid process 2 11 1£^
'Abnormalities.
Source: Starke et al. (1982).
concentration of 10 iiL/plate was cytotoxic to all five strains and 1.0 pL/plate
was cytotoxic to strain TA1535. The same Salmonella strains exposed to red
phosphorus at levels up to 10 mg/plate with or without metabolic activation did
not display any mutagenic activity (McGregor, 1980).
Escherichia coli was used in tests for lethality due to DNA damage. No
toxic effects were found at exposure levels of 10 mg/plate of red phosphorus.
Negative results were obtained in mitotic recombination tests in the yeast
Saccharomyces cerevisiae exposed to red phosphorus (McGregor, 1980).
43
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White phosphorus/felt smoke condensate was tested for its ability to
induce mutations in fruit flies. Exposure to concentrations of 0.01 to 10
percent in food for 42 hours did not induce sex-linked recessive mutations on
the X-chromosome of Drosophila melanogaster. Nevertheless, an exposure-
dependent increase in toxicity was observed; concentrations of 10 percent
produced 100 percent mortality within 72 hours, 1 percent concentration
produced 11 percent mortality, 0.1 percent concentration produced 2 percent
mortality, and 0.01 percent caused no mortality (Brown et al., 1980).
Starke et at. , (1982) conducted studies to determine if white phosphorus/-
felt smoke produced dominant lethal mutations in rats. Fertile male rats were
exposed for 15 minutes/day, 5 days/ week for 10 weeks to smoke concentra-
tions of 0, 500, or 1,000 mg/m3. The rats were mated during exposure to the
highest concentration. For the most part, there were no significant differences
between controls and animals exposed to smoke. More resorptions were
observed in females mated with males exposed to the lowest concentration
than in females mated wtih control or high-exposed animals. Since this
parameter was not concentration-dependent, it was not significantly related to
exposure. Therefore, white phosphorus smoke at concentrations of 500 or
1,000 mg/m3 did not induce dominant mutations in rats.
3.6.2 Inorganic Phosphorus Compounds
Only limited information was found in the published literature on the
mutagenic activity of the inorganic phosphorus compounds. Using a modified
Ames test, phosphorus trichloride was found not to be mutagenic in
Salmonella typhimurium (McMahon et al., 1979). In a study by Roshchin and
Molodkina (1977) exposure to 1.34 mg/m3 (0.2 ppm) phosphorus oxychloride
produced increased numbers of chromosomal aberrations and cytostatic
activity in rats. However, at a lower exposure level (0.48 mg/m3; 0.08 ppm),
the chromosomal aberrations did not differ significantly from those observed in
controls.
3.7 Carcinogenicity
3.7.7 Elemental Phosphorus
No studies were found specifically addressing the carcinogenic potential
of the elemental phosphorus compounds in animals. However, neoplastic
lesions were not observed in rats administered white phosphorus orally (0.2 to
1.6 mg/kg/day) or subcutaneously (0.05 to 3.5 mg/kg/day) or in guinea pigs
administered white phosphorus subcutaneously (0.05 to 0.4 mg/kg/day) over
their entire lifetime (Fleming et al., 1942).
3.7.2 Inorganic Phosphorus Compounds
The only studies on the carcinogenic potential of the inorganic
phosphorus compounds found in the published literature were two studies on
the oral administration of phosphine via feed. Phosphine was found not to be
carcinogenic in rats under the conditions of the studies. Refer to Section 3.4.2
for details of the studies.
44
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3.8 Effects on humans
3.8.1 Elemental Phosphorus
No information was found in the published literature regarding the effects
of inhalation or ingestion of red phosphorus and only limited information on the
effects of inhalation of white phosphorus in humans. Exposing 108 men to 87
to 1,770 mg/m3 of white phosphorus smoke (length of exposure not given)
caused throat irritation and coughing. This experiment led Cullumbine (1944,
as reported in Wasti et al., 1978) to establish 700 mg/m3 as a minimum
harassing exposure level in working men and 1,000 mg/m3 in resting men.
White and Armstrong (1935) carried out a very limited experiment in
which male human subjects were exposed to white phosphorus smoke in a
chamber. The concentrations ranged from 185 mg/m3 to 592 mg/m3 and the
exposure times ranged from 5 to 15 minutes. Irritation of the throat, especially
while talking was- the most common effect. Coughing was frequently reported,
in addition to congestion, tightness in the chest, and nasal discharge. The
authors suggested that exposure to 514 mg/m3 approached the maximum
concentration at which humans may be exposed for 15 minutes without
encountering serious effects.
Walker et al. (1947) reported the effects of inhalation of white phosphorus
smoke on four women exposed during an accident in a plant processing white
phosphorus munitions. Other components in the smoke, in addition to those
produced by the burning of white phosphorus, may have been present,
although no information on these components was available. The women were
exposed for 15 to 20 minutes in a closed room that rapidly filled with dense
smoke. All of the women developed respiratory symptoms: choking
sensations, feelings of suffocation, sense of tightness in the chest, coughing,
tenacious sputum production, rales, sore throat, and hoarseness. The women
who became hoarse also showed erythema and edema of the larynx and vocal
cords. Injury apparently extended well into the bronchi since these patients
expectorated bronchial casts containing necrotic superficial layers of bronchial
epithelium. Chest X-rays revealed patchy areas of infiltration that cleared
within 5 to 10 days. Coughing arid expectoration subsided within several days
but hoarseness persisted long after other evidence of respiratory tract irritation
disappeared.
Five males were exposed to white phosphorus vapors composed of 35
mg/m3 of phosphorus and 22 mg/m3 of phosphorus pentoxide at an industrial
site (Aizenshtadt et al., 1971). They were exposed for 2 to 6 hours at 7-hour
intervals (total exposure time not given) while cleaning a tank of "Cottrell Milk"
(an aqueous suspension- of phosphorite, quartzite, and coke dust) by hand
without protective equipment. Within 6 to 20 hours, all developed symptoms of
malaise, weakness, dry cough, and slight hyperthermia. The next day,
dyspnea, cough with thick discharge, high fever (5/5), headache, vertigo, chest
pains(2/5), rhinitis, and epistaxis (1/5) were noted. Further examination
revealed hyperemia of the face and pharynx (2/5), multiple diffuse rales (5/5),
bubbling rales (3/5), tender liver upon palpation (4/5), and hepatomegaly (1/5).
Laboratory tests showed evidence of leukocytosis with relative
lymphocytopenia, increased erythrocyte sedimentation rate, normal bilirubin
and residual nitrogen, reduced cholesterol, and dysproteinemia. Erythrocyte
acetylcholinesterase was reduced by 17 percent and plasma
acetylcholinesterase by 35 percent.
• 45
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According to Sollmann (1957) the estimated minimal lethal dose of
elemental (yellow or white) phosphorus to humans is 50 mg (0.7 mg/kg), most
often 100 mg (1.4 mg/kg), but 15 mg (0.2 mg/kg) may cause serious toxic
effects. These doses were estimated from patients who did not receive
medical treatment after intoxication. Because treatment changes both the
prognosis and the lethality of a particular dose of elemental phosphorus
(Poison et al., 1983), humans have recovered from larger doses. Information
on the acute oral effects of phosphorus has come primarily from analyzing
cases of accidental or intentional ingestion of yellow phosphorus contained in
preparations such as pesticide paste, fireworks, and match tips. The major
targets of elemental phosphorus poisoning are the gastrointestinal tract, brain,
liver, kidney, and cardiovascular system (McCarron et al., 1981).
The classical description of acute oral phosphorus poisoning divides the
symptoms into three stages: initial (stage 1), latent (stage 2), and systemic
(stage 3) (McCarron et al., 1981; Hayes, 1982). Stage 1 symptoms, attributed
to local irritation of the gastrointestinal tract, include nausea, vomiting,
abdominal pain, thirst, garlic breath, hematemesis, and slight diarrhea. Stage 2
symptoms are described ^s a period of well being, during which there is an
abatement of symptoms. Stage 3 symptoms include the reappearance of
more severe nausea, vomiting, and abdominal pain, and the appearance of
hepatomegaly, jaundice,'-CNS injury, hemorrhage, oliguria, peripheral vascular
collapse, coma, and death (Cameron and Rentoul, 1963; McCarron et al.,
1981; Hayes, 1982). Death in the third stage usually results from liver failure,
but also may be due to cardiovascular collapse or kidney failure (Diaz-Rivera
et al., 1950). The length of each stage is variable: stage 1 lasts from 24 to 48
hours, stage 2 from a few hours to as long as 10 days, and stage 3 may begin
within the first 4 to 5 days and last for a variable length of time depending
upon the degree of intoxication (Cameron and Rentoul, 1963; Hayes, 1982).
Table 3-5summarizes the gross symptoms in several case studies of patients
who died or recovered after ingesting elemental phosphorus.
The relationship between dose of phosphorus and mortality rates in the 56
cases studied by Diaz-Rivera et al. (1950) is presented in Table 3-6. For the
most part, doses of 1.57 g or more were fatal with only 2 out of 21 patients
surviving ingestion of 1.57 g of phosphorus. Doses of 0.78 g or less were
associated with a high survival rate, with 27 of 33 patients surviving.
Hepatomegaly is one of the characteristic symptoms of phosphorus
poisoning. Of the 56 cases reported by Diaz-Rivera et al. (1950), 41 developed
hepatomegaly. Impending death was associated with patients who developed
this symptom within the first 48 hours (52 percent mortality), whereas all of
those who developed the symptom after 48 hours survived. The livers of
patients who ingested phosphorus were yellow, with areas of necrosis. They
also had slight to moderate leukocytic infiltration, fibrosis, and extensive fatty
degeneration with vacuolization. The pathological changes may cause loss of
the lobular structure of the liver (Dwyer and Helwig, 1925; LaDue et al., 1944;
Wechsler and Wechsler, 1951; Cameron and Rentoul, 1963).
Myocardial damage induced by acute phosphorus poisoning consisted of
abnormalities in the electrocardiograms (EKG), prolongation of QT interval, ST
and T wave changes, abnormalities in rhythm, and low voltage of QRS
complexes (Diaz-Rivera et al., 1961). Pietras et al. , (1968) observed that EKG
abnormalities were reversible. Microscopic examination of the heart showed
fatty degeneration, interstitial edema without cellular infiltrates, and cells with
vacuolated cytoplasm (Diaz-Rivera et al., 1961; Cameron and Rentoul, 1963).
Wechsler and Wechsler (1951) also found evidence of myocardial necrosis.
46.
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Table 3-6
Dose (g)
6.30
4.62
1.57
0.78
0.39
0.19"
Oral Toxicity of Elemental
Phophorus in Humans
No. Cases
1
1
21
18
14
1
Mortality (%)
100
100
90
16.3
14.3
100
"Patient refused medical treatment.
Source: Diaz-Rivera et al.. (1950).
The prevalence of abnormalities in EKG's in relation to the dose of
phosphorus was 33 percent of 6 patients ingesting less than 0.38 g, 45
percent of 11 patients ingesting 0.39 to 0.74 g, 56 percent of 23 patients
ingesting 0.75 to 1.49 g, and 67 percent of 10 patients ingesting 1.57 g or
more (Diaz-Rivera et al., 1961). Myocardial damage was also observed in a
16-year-old female who ingested 1.11 g of phosphorus and died within 33
hours (Talley et al., 1972), in a 30-year-old male who ingested approximately
1.18 g and recovered (Pietras et al., 1968), and in a 21-year-old male who
ingested 1.5 g and recovered (Newburger et al., 1948).
Cushman and Alexander (1966) reported a case of acute phosphorus
poisoning with hypocalcemia and hypophosphatemia. Increased urinary
excretion of calcium and phosphate in relation to the measured oral intake
suggested a disturbance of the proximal tubular function. Neuropathology
characterized by lipid accumulation within neurons may occur in humans
within hours of yellow phosphorus ingestion (O'Donoghue, 1985).
Because white phosphorus ignites spontaneously in air, it causes severe
bums if it comes in contact with the skin. Phosphorus burns have been
sustained in industrial accidents and in the battlefield (Walker et al., 1947;
Summerlin et al., 1967; Berkowitz et al., 1981). Walker et al. (1947) evaluated
27 casualties resulting from four accidents in plants processing white
phosphorus munitions at Edgewood Arsenal, MD. Of the 27 casualties, 9 with
third degree burns over 90 percent or more of the body surface died almost
immediately, 3 with third degree burns over 35 to 65 percent of the body
surface died within 19 hours, and 15 with third degree burns over up to 19
percent and different amounts of second degree burns survived. Both second
and third degree burns were similar to thermal burns. Systemic effects due to
white phosphorus burns were not noted; liver damage, as indicated by serum
bilirubin levels and bromosulfalein retention studies, was not observed; blood
sugar and serum calcium were normal; phosphorus excretion was reduced
rather than elevated.
During a 17-year period (1969 through 1985), 49 patients were admitted to
the U. S. Army Institute of Surgical Research for chemical burns resulting
from exposure to white phosphorus (Mozingo et al., 1988). Most of the injuries
occurred in Vietnam. Systemic toxicity was noted in two cases resulting from
cutaneous absorption of copper sulfate used to neutralize white phosphorus
burns. Compared with other chemical burns, white phosphorus had more
associated injuries and required longer hospital stays.
48
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Summerlm et al. (1967) described three cases of white phosphorus burns
accompanied by massive hemolysis. Case 1 was a 25-year-old male who had
sustained burns over 29 percent of his body surface; case 2, a 46-year-old
male who had burns over 12.5 percent of his body surface; and case 3, a 24-
year-old male who had burns over 7.5 percent of his body surface. In each
case hemoglobinemia, hemoglobinuria, hematuria, bilirubinemia, mild (case 2
and 3) to severe (case 1) hypocalcemia, oliguria, and renal failure were
observed. Case 2 showed evidence of hyperphosphatemia. Case 1 also
showed evidence of myocardial ischemia, which disappeared on the fifth
hospital day. Massive hemolysis could not definitely be attributed to systemic
effects of white phosphorus burns.
Chronic exposure of humans to white phosphorus causes a characteristic
lesion, necrosis of the jaw, sometimes referred to as phosphorus necrosis or
"phossy jaw" (Miles, 1972). Because white phosphorus was used in the lucifer
match industry, numerous cases of this occupational disease appeared during
the 19th and the early part of the 20th century. It was the phosphorus-related
necrosis of the jaw which lead to international legislation prohibiting the
manufacture, sale, and transport of phosphorus matches in several European
countries in 1906. Phosphorus necrosis of the jaw was also associated with the
manufacture of fireworks and the production of phosphorus (Ward, 1926).
Although Ward (1926) and Oliver (1938) considered phosphorus necrosis due
to industrial sources as a disease of the past, subsequent cases were reported
by Kennon and Hallam (1944), Heimann (1946), and Hughes et al. (1962). A
very recent case, although not of industrial origin, was described by Jakhi et
al. (1983).
In a survey of 15 matchmaking factories in the United States from 1908 to
1909, 65 percent (2,334) of 3,591 workers were exposed to phosphorus. More
than 150 cases (four were fatal) of phosphorus necrosis were discovered; the
majority were women and children less than 16 years old. In three fireworks
factories employing 71 workers, 14 cases (two fatal) were discovered (Ward,
1926).
According to Sollmann (1957), the incidence of phosphorus necrosis was
less than 5 percent of those exposed to phosphorus. While the disease
affected relatively few people, it-was the most disfiguring of all occupational
diseases in the 19th and early 20th century (Ward, 1926). The estimated
mortality rate from phosphorus necrosis was 20 percent (Hunter, 1969). The
clinical symptoms usually begin with a tooth ache, more often in the lower jaw,
followed by suppurative ulceration of the gums around a diseased tooth or a
root abscess which does not heal after extraction, with suppurating fistula, and
progressive necrosis of the maxilla (Sollmann, 1957). The progress of the
disease, in earlier cases, resulted in the loss of large portions of the jawbone
during the formation of large sequestrae; consequently, the facial structures
became grossly disfigured. Sequestrae are pieces of dead bone that become
separated from healthy bone during the process of necrosis. The more recent
cases of phosphorus necrosis were very mild compared to the disease in the
last century (Hughes et al., 1962).
The cause of phosphorus necrosis is still questionable; phosphorus itself
(Oliver, 1938; Hughes et al., 1962), combustion products (fumes, vapors, or
smoke) made up of oxides of phosphorus (Hughes et al., 1962; Miles,-1972),
phosphoric acid, and phosphorous acid (Oliver, 1938) each have been
implicated as the causative agent. Some individuals are more susceptible to
phosphorus necrosis than others, particularly those with poor oral hygiene,
caries, a tooth extracted during exposure to phosphorus, or other dental
diseases (Ward, 1926; Kennon and Hallam, 1944; Miles, 1972). In recent
49
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years, strict medical and dental surveillance, early diagnosis, and treatment
have caused reductions in both the incidence and the severity of this
occupational disease.
Fragility of long bones which led to bone fractures in lucifer match
workers under relatively so-called "trifling" circumstances suggest that
phosphorus may act by a systemic route (Oliver, 1938). Also, the delayed
onset of phosphorus necrosis after workers are removed from the source of
exposure, is suggestive of a systemic action (Hughes et al., 1962).
The airborne levels of phosphorus were not known in the case histories of
phosphorus necrosis presented in the literature; therefore, the disease process
could not be correlated with concentrations of phosphorus in the air. The
duration of exposure prior to onset of necrosis of the jaw was known in most
cases but varied considerably. Ward (1926) observed that exposure ranged
from less than 3 months to 12 years prior to the onset of the disease. In two
fatal cases, one was exposed for 6 years and the other for 2 years. The
duration of the illness ranged from about 5 months, in one worker employed
for 10 years, to 6 years in another worker employed for 12 years. In the 11
cases reported by Legge (1920) the duration of exposure ranged from 5
months to 23 years. The duration of the illness ranged from 2 months to 5
years. The duration of exposure in the cases described by Kennon and Hallam
(1944) ranged from 13 months to 10 years. In three cases the disease did not
reveal itself until after the worker had left the phosphorus process.
Hughes et al. (1962) studied 48 healthy men working in a phosphorus
plant to evaluate the systemic effects of phosphorus exposure. The duration of
exposure ranged from 1 to 17 years. The 28 control subjects were not
perfectly age matched. Statistical differences were not found in the
hematological evaluation or in plasma levels of inorganic phosphorus, alkaline
phosphatase, calcium, and magnesium; radiographs did not reveal differences
in density of bones.
Evidence of functional liver damage and possible bone abnormalities are
reported in a more recent Russian study of 337 workers engaged in the
production of yellow phosphorus (Ozerova et al., 1971, as reported in Idler et
al., 1981). Exposure ranged from 3 to 5 years at maximal permissible air
concentrations and occasional elevated levels of phosphorus. The maximum
allowable level in the Soviet Union is 0.03 mg/m3 (International Labour Office,
1980).
No information was found in the published literature on the carcinogenic
potential of elemental phosphorus. Therefore, according to the U. S.
Environmental Protection Agency's proposed guidelines for carcinogenicity,
elemental phosphorus is classified under Group D, not classifiable as to
human carcinogenicity.
3.8.2 Inorganic Phosphorus Compounds
Harger and Spolyar (1958) reported that 59 cases of phosphine poisoning,
including 26 deaths, have been recorded between 1900 and 1958. Phosphine
poisonings have been reported in people exposed to releases from ferrous
alloys stored on freight boats, in occupants of apartments near fumigated grain
elevators, in welders breathing acetylene from portable generators, and in
submarine crews carrying sodium phosphide for the production of warning
lights formines (Harger and Spolyar, 1958).
The inhalation of phosphine is usually an accidental occurrence and its
disagreeable odor is quickly apparent. However, the odor threshold of 2.0 to
3.0 mg/m3 (Sax, 1986) does not necessarily provide an adequate warning of
50
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the presence of dangerous amounts (Heimann, 1983). The acute hazard levels
of phosphine in humans are summarized in Table 3-7.
Wilson ,et al. (1980) describe the acute phosphine poisoning of two
children and 29 of 30 crew members caused by the leakage of phosphine
fumigant from an inadequately sealed hold aboard a grain freighter. One child
died. The prevailing symptoms which occurred about four days after
fumigation were headache, fatigue, nausea, vomiting, cough, and shortness of
breath. Others included jaundice, paresthesias, ataxia, intention tremor, and
diplopia. Postmortem examination of the child revealed focal myocardial
infiltration with necrosis, pulmonary edema, and widespread small-vessel
injury. Indications of myocardial injury were also noted in the surviving child.
Urinalysis and liver function tests of the crew members showed the following
abnormalities; occult blood in the urinary tract, bilirubinuria, and elevated
serum transaminase and lactic dehydrogenase levels. Abnormal clinical and
laboratory findings in the affected individuals returned to normal six days after
hospitalization. The severity and duration of the illness was positively
correlated with having lived or worked in areas of the ship with high phosphine
concentrations. In some areas of the ship the concentration of phosphine
greatly exceeded the TLV value of 0.42 mg/m3 or the odor threshold of 2.0 to
4.0 mg/m3. Phosphine levels in representative areas of the ship were: 28.0 to
42.0 mg/m3 in a void space on the main deck, 11.0 to 14.0 mg/m3 near a
hatch, and 0.7 mg/m3 in some living quarters.
Jones et al. (1964) reported that most of 67 grain fumigators,
intermittently exposed to phosphine during fumigation with aluminum
phosphide and shipping of bulk wheat, exhibited symptoms of phosphine
poisoning in varying degrees. The symptoms fell into three main categories:
gastrointestinal (diarrhea, nausea, epigastric pain, and vomiting),
cardiac/respiratory (tightness of chest, breathlessness, chest pain, palpitations,
and severe retrosternal pain), and central nervous system (headache,
dizziness, and staggering gait). In half of those affected, the symptoms
appeared immediately, while others experienced a delay of several hours to
two days. There was no evidence of chronic effects and no tendency to
develop adaption. Concentrations of 0.4 mg/m3 or less sometimes produced
headache but no other symptoms during intermittent exposures over several
months. The measured phosphine concentrations in the breathing zone of
workers ranged from 0 to 49.0 mg/m3, but averaged below 14.0 mg/m3 in
most cases. Employees in shipping areas experienced the highest measured
concentrations of phosphine, with exposure duration greater than 8 hours/day
for several days.
The pattern of illness in the two studies discussed above resembled that
found in crew members of a British submarine which carried sodium
phosphide for the production of mine warning lights (Glass, 1957). The
symptoms included greyish pallor, dizziness, shortness of breath, vomiting,
tightness of the chest and palpitations, spasmodic attacks of dyspnea, blurred
vision, and collapse. Liver function tests were normal. The symptoms were
considered mild and were attributed to short exposure times and low
phosphine levels (phosphine levels on the submarine were not determined).
Misra et al. (1988a) evaluated the health effects of occupational exposure
to phosphine resulting from grain fumigation in India. Twenty-two workers
(mean age 48 years, mean duration of exposure 11.1 years) were examined.
The phosphine concentration in the work environment ranged from 0.23 to
2.81 mg/m3. Exposure to the chemical caused mild to moderate respiratory,
neurological, and gastrointestinal symptoms which were transient. They
51
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Table 3-7 Acute Hazard Levels of Phosphine in Humans
Concentration
1.4 mg/m3
35 mg/m3
70 mglm3
9.8 mg/m3
Exposure
Period
7 hf ix/week
1 hr ix/week
0.1 hr ix/week
Several hr
Data
Maximum safe exposure
Maximum safe exposure
Maximum safe exposure
Maximum tolerated
280 mglm3
2,800 mg/m3
Few min
concentration
Immediately dangerous to
life and health (1DLH)
Lethal
Source: Sax (1986).
included cough, dyspnea, tightness of the chest, headache, giddiness,
numbness, lethargy, anorexia, and epigastric pain.
Phosphine may be released during the generation of acetylene from
impure calcium carbide (Sittig, 1985). Harger and Spolyar (1958) described
the death of an acetyfene operator from pulmonary edema. The probable
cause of death was exposure to phosphine at levels of about 11.0 mg/m3 for 1
to 2 hours/day for 5 to 6 weeks.
A case of human oral poisoning by phosphine, with suicidal intent, has
been reported by Zipf et al. (1967). It involved a 25-year-old man who
swallowed six aluminum phosphide tablets dissolved in water. If all the
material had been retained, about 6,000 mg of phosphine could have been
released. The immediate effects were severe substernal and upper abdominal
pain, intolerable burning sensation of the whole body, severe vomiting, and
loss of consciousness. On the day after ingestion there was hematuria,
leukocyturia, and proteinuria. From the fourth day on, uremia and pulmonary
edema were observed. Other major complications included damage to the
heart, brain, and liver (scleral icterus and hepatomegaly).
Another study by Misra et al. (1988b) examined eight cases of phosphine
poisoning in India following ingestion of aluminum phosphide tablets with
suicidal intent. The mean age of the patients was 23 years. Six patients died
shortly after ingestion of aluminum phosphide with peripheral vascular failure
as the major course of death. Phosphine poisoning was characterized by
vomiting, restrosternal and abdominal pain, peripheral vascular failure, cardiac
arrhythmia, and altered consciousness. One patient developed jaundice and
another developed acute renal failure. Postmortem examination of two patients
revealed pulmonary edema; desquamation of the lining of bronchioles;
gastrointestinal mucosal congestion; petechial hemorrhages of the liver and
brain; vacuolar degeneration of hepatocytes; dilatation and engorgement of
hepatic central veins, sinusoids, and areas showing nuclear fragmentation.
The possibility of chronic phosphine poisoning as a result of extended
exposure has been mentioned by some authorities (Beliles, 1981; Torkelson et
al., 1966), but no such cases have been documented in the available literature.
Phosphoric acid may cause irritation of the upper respiratory tract, eyes,
and skin; it also may produce skin burns and dermatitis (Sittig, 1985). At a
concentration of 1.0 mg/m3, the Federal standard, phosphoric acid mist is
irritating to unacclimated workers but is easily tolerated by acclimated workers
52
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(Siffig, 1985). The World Health Organization (1986) indicates that about 0,5
mg/m3 of phosphoric acid is irritating to unacclimatized individuals.
A single drop of orthophosphoric acid (0.16 M, buffered to pH 2.5) caused
a moderate brief stinging but no injury in the human eye. The same solution
adjusted to a pH of 3.4 elicited no discomfort (Grant, 1974).
In a human experiment, 50 percent phosphoric acid was applied to the
gingival tissue and teeth of 26 orthodontic patients (ages 12 to 16 years). The
acid was in contact with the gingiva and teeth for 90 seconds and then rinsed
off. After a period ranging from one to seven days, examination of the treated
tissues did not show any demonstrable effect resulting from contact with
phosphoric acid (Forsberg, 1982).
In a related study, Johnson et al. (1970) tested the effects of phosphoric
acid, a component of silica cement for dental fillings, on dental pulp. Sound
teeth, exposed to 6 M phosphoric acid buffered to a pH of 3.5 or 5.0 or to
distilled water, revealed the same extent of inflammatory changes in dental
pulp. Exposure to the acids, however, produced an increasing number of
inflammatory responses as the thickness of dentine protecting the pulp
decreased.
A case report indicates that phosphoric acid ingestion may produce
metabolic abnormalities in addition to local caustic effects (Caravati, 1987). A
64-year-old man intentionally ingested 3 to 4 ounces of a porcelain and metal
cleaner containing phosphoric acid. He developed hyperphosphatemia,
hypocalcemia, and systemic metabolic acidosis. The caustic effects were mild
and consisted of burning sensation in the throat and mild mucosal burns of the
gastrointestinal tract.
Phosphorus trichloride in liquid as well as vapor form is highly irritating to
the skin and mucous membranes, respiratory tract, and eyes. Severe acid
, burns can occur (Grant, 1974; Beliles, 1981).
Occupational exposure to phosphorus trichloride during its manufacture
resulted in acute and subacute adverse health effects in workers who had
been exposed to the chemical from 1951 to 1952 (Sassi, 1953). Under normal
working conditions, workroom levels were 10 to 20 mg/m3 but reached levels
as high as 80 to 150 mg/ms at times when the plant was out of order. The
acute effects, beginning after 2 to 6 hours of exposure, were characterized by
a burning sensation in the eyes and throat, photophobia, feeling of chest
oppression, dry cough with mucous membrane irritation, and slight bronchitis.
The symptoms disappeared after 3 to 6 days. After exposure for 1 to 8 weeks,
the workers developed slight pharyngeal irritation, coughing, catarrh, nocturnal
dyspnea, and pronounced bronchial asthma. The symptoms lasted for 10 to
15 days, and had a tendency to recur and develop into chronic asthmatic
bronchitis with emphysema. Slight rises in temperature accompanied by
moderate leukocytosis with neutrophilia were frequently found. Chronic
exposure for 1 to 2 years produced pulmonary emphysema.
Wason et al. (1984) studied 17 patients who .were exposed to phosphorus
trichloride spilled in a railroad accident. Cleanup attempts with water led to the
release of phosphorus trichloride, phosphoric acid, hydrochloric acid, and
phosphorus oxides. At the time of the accident the patients experienced the
following symptoms: burning and watery eyes, blurred vision, skin and throat
irritation, cough, shortness of breath, and headache. The study could not
distinguish the effects of exposure to phosphorus trichloride from the
additional irritating reaction products. Screening tests of liver function showed
a transient elevation of lactic dehydrogenase in six patients. Pulmonary
function tests revealed statistically significant decreases in vital capacity,
maximal breathing capacity, forced expiratory volume in one second, and
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maximal expiratory flow rate at 25 percent vital capacity in those closest to the
accident site. The pulmonary effects were directly correlated with the distance
from the accident and duration of exposure. Follow-up tests of seven patients
one month later showed improved pulmonary function.
Because of its fuming and deliquescent properties, phosphorus
pentachloride is very irritating and corrosive to the skin; eyes, and all mucous
membranes, including the lungs (Boenig et al., 1982; Beliles, 1981). The
chemical can cause serious skin burns by reacting with moisture with the
liberation of heat and formation of hydrochloric and phosphoric acids (Boenig
etal., 1982).
Eleven workers accidentally inhaled a gaseous mixture of hydrogen
chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride,
and oxalic acid as a result of an explosion in a factory where the chemicals
had been manufactured (Rosenthal et al., 1978). Mucosal irritation was
reported during the time period required for escape from the enclosed area
(1.5 to 2 minutes). The major symptoms were hoarseness, wheezing, cough,
and shortness of breath. Evidence of obstruction of the airways consisted of
mild interstitial and alveolar edema, diffusion defects, and hypoxemia. A few
patients had moderately severe conjunctivitis. Leukocytosis was found in four
patients, slightly elevated lactic dehydrogenase levels in three, traces of
albumin in urine in one, and erythrocytes in the urine in two others. In most
cases, the pulmonary disorders cleared within a few days. In one most
severely affected patient, abnormal pulmonary function persisted for two
years. Each of the components of the gaseous mixture inhaled (4/5
compounds contained chlorine) is irritating to the mucous membranes and
may produce respiratory effects; thus, the toxic effects could not be attributed
simply to the two phosphorus compounds.
One report indicates that inhalation of phosphorus pentachloride may
cause damage to the kidneys (Von Oettinger, 1958). The compound
reportedly produced acute nephritis with oliguria (no details of exposure
conditions were provided).
Roshchin and Molodkina (1977) found that the threshold limit for the
irritating effects of phosphorus pentachloride in humans and laboratory
animals are similar, namely about 10.0 mg/m3. Based on these findings, they
suggested a highest permissible concentration in the work place of 0.2 mg/m3,
which is identical to that proposed for phosphorus trichloride.
Phosphorus oxychloride presents similar hazards as phosphorus
trichloride and phosphorus pentachloride. The vapors of this readily volatilizing
chemical are very irritating to the eyes, skin, and mucous membranes. Severe
burns result from direct contact with the liquid. Inhalation can cause pulmonary
edema (Boenig et al., 1982).
A survey conducted by NIOSH at a manufacturing plant indicates that
workers exposed to phosphorus trichloride and phosphorus oxychloride may
experience intermittent respiratory distress (wheezing, chest tightness, and
breathlessness). In a follow-up study covering a two-year period, half of the
exposed workers of the original study reported a higher incidence of
intermittent respiratory distress, but there was no significant impairment of
pulmonary function when compared with unexposed individuals (Moody,
1981).
Mclaughlin (1946) reported two cases of slow healing burns of the cornea
in humans produced by exposure to phosphorus oxychloride. As with
exposure to phosphorus trichloride and pentachloride, Roshchin and
Molodkina (1977) found that the threshold for the irritant effects of phosphorus
54
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oxychforide are similar in humans and rats. However, phosphorus oxychloride
is more irritating, with a threshold exposure concentration of 1 mg/m3.
The dust or fume of phosphorus sesquisulfide may be irritating to the
eyes, respiratory tract, and skin (Beliles, 1981). Several cases of allergic
contact dermatitis caused by phosphorus sesquisulfide contained in safety
matches have been reported in the literature (Burgess, 1951; Chiarenza and
Gallone, 1981; Steele and Ive, 1982; White and Rycroft, 1983; Burge and
Powell, 1983; Ayala et al., 1987; Pena Payero et al., 1985). Burgess (1951)
described primary dermatitis of the face and area around the eyes in two
women due to contact with matches or hypersensitivity to fumes of match tips
containing phosphorus sesquisulfide. Daily lighting of matches resulted in
recurring episodes of edematous dermatitis over a period of several years. In
one case, the episodes were accompanied by prostration, vertigo, loss of
appetite, nausea, and vomiting. In both cases, a marked loosening of the teeth
was observed. The author suggested that the dental changes are similar to
those seen in individuals exposed to elemental phosphorus. Both local and
systemic symptoms disappeared on discontinuing the use of matches.
Burge and Powell (1983) described a patient with dermatitis, traced to
matches, who developed both immediate and delayed hypersensitivity
reactions to phosphorus sesquisulfide. Symptoms included generalized
pruritus, hand eczema, conjunctivitis, and eyelid swelling. The skin lesions
cleared when the patients avoided matches.
Recurrent facial eczema (extending over a period of 9 months to 5 years)
in three women exposed to phosphorus sesquisulfide matches is described by
Steele and Ive (1982). Two of the patients were smokers and match users, the
third was a nonsmoker but exposed to the allergen in her work environment.
An allergic eczematous reaction and immediate hypersensitivity to
phosphorus sesquisulfide matches occurred in a 34-year-old male and
affected the face, thigh, penis, and fingers. Facial irritation and wheezing
episodes were sometimes noticed after periods of about 1 hour when the
patient was in areas where others had been smoking (White and Rycroft
1983).
Intense itching with scaly patches in areas on leg and chest where
matches come in contact with skin were described by Chiarenza and Gallone
(1981) in a patient who carried matches in his pockets over an extended
period of time. Lymphomatoid contact dermatitis (characterized by infiltrated
plaque-like lesions with some similarities to lymphoma or mycosis fungoides)
resulting from exposure to phosphorus sesquisulfide as an allergen is reported
by Ayala et al. (1987). A 62-year-old farmer had a 2-year history of recurring
pruritic eruptions of the face and plaque-like lesions on both outer thighs. The
condition was attributed to matches (containing phosphorus sesquisulfide) in
trouser pockets and use of fertilizers and fungicides, probably containing
phosphorus as a component.
Pena Payero et al. (1985) reported a case of eczematous dermatitis of the
thighs in a 32-year-old male from contact with matches in trouser pockets.
Also present were scaly erythematous lesions on the eyelids and back of the
hands. A patch test with 0.5 percent phosphorus sesquisulfide produced an
immediate severe urticarial response and an eczematous reaction at 48 hours
which lasted for several days. The patient noted an intense taste of matches
several minutes after the patch test was applied.
No information was found in the published literature on the carcinogenic
potential of the inorganic phosphorus compounds (phosphine, phosphoric
acid, phosphorus trichloride, phosphorus pentachloride, phosphorus
55
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oxychloride, and phosphorus sesquisulfide). Therefore, these compounds are
classified as Group D carcinogens, not classified as to human carcinogenicity.
56
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