United States Office of Heslth sod fpa boo/6—89/07?
Environmental Protection Environmental Assessment , ",«««
Agency Washington DC 20460 August 1989
Research and Development
SEFA
Summary Review of Health Effects
Associated with Elemental and
Inorganic Phosphorus Compounds:
Health Issue Assessment
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EPA
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^ EPA 600/8-89/072
August 1989
Summary Review of Health Effects
&
Associated with Elemental and
£ Inorganic Phosphorus Compounds:
* Health Issue Assessment
^ us EPA
Headquarters and Chemical Libraries
EPA West Bldg Room 3340 n
Mailcode 3404T nSp^SitOfV Mstdfti
Co 1301 Constitution Ave NW n /« ,
Washington DC 20004 r8!7113080! Coifed'
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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.
ii
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CONTENTS
Pa^e
TABLES Y
PREFACE V.
ABSTRACT V11
AUTHORS AND'REVIEWERS viil
1. SUMMARY AND CONCLUSIONS 1"1
1.1 ELEMENTAL PHOSPHORUS 1-1
1.2 INORGANIC PHOSPHORUS COMPOUNDS 1-6
2 BACKGROUND INFORMATION 2-1
2.1 CHEMICAL CHARACTERIZATION AND MEASUREMENT 2-1
2.1.1 Elemental Phosphorus 2-1
2.1.2 Inorganic Phosphorus Compounds 2-2
2.2 PRODUCTION AND USES 2-3
2.2.1 Elemental Phosphorus 2-3
2.2.2 Inorganic Phosphorus Compounds 2-4
2.3 ENVIRONMENTAL RELEASE AND EXPOSURE 2-6
2.3.1 Elemental Phosphorus 2-7
2.3.2 Inorganic Phosphorus Compounds 2-9
2.4 ENVIRONMENTAL FATE 2-10
2.4.1 Elemental Phosphorus 2-10
2.4.2 Inorganic Phosphorus Compounds 2-11
2.5 ENVIRONMENTAL EFFECTS 2-11
2.5.1 Elemental Phosphorus 2-11
2.5.2 Inorganic Phosphorus Compounds 2-14
3. HEALTH EFFECTS 3-1
3.1 PHARMACOKINETICS AND METABOLISM 3-1
3.1.1 Elemental Phosphorus 3-1
3.1.2 Inorganic Phosphorus Compounds 3-4
3.2 BIOCHEMICAL EFFECTS 3-5
3.2.1 Elemental Phosphorus 3-5
3.2.2 Inorganic Phosphorus Compounds 3-6
3.3 ACUTE TOXICITY 3-7
3.3.1 Elemental Phosphorus 3-7
3.3.2 Inorganic Phosphorus Compounds 3-12
3.4 SUBCHRONIC AND CHRONIC TOXICITY 3-15
3.4.1 Elemental Phosphorus 3-15
3.4.2 Inorganic Phosphorus Compounds 3-20
3.5 TERATOGENICITY AND REPRODUCTIVE EFFECTS 3-22
3.5.1 Elemental Phosphorus 3-22
3.5.2 Inorganic Phosphorus Compounds 3-24
3.6 MUTAGENICITY 3-24
3.6.1 Elemental Phosphorus 3-24
3.6.2 Inorganic Phosphorus Compounds 3-25
3.7 CARCINOGENICITY 3-25
3.7.1 Elemental Phosphorus Compounds 3-25
3.7.2 Inorganic Phosphorus Compounds 3-2o
• • •
m
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CONTENTS (continued)
Page
3.8 EFFECTS ON HUMANS 3-26
3.8.1 Elemental Phosphorus 3-26
3.8.2 Inorganic Phosphorus Compounds 3-33
4. REFERENCES 4-1
iv
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TABLES
Number Page
1-1 Summary of significant toxic effects of elemental
phosphorus compounds 1-3
1-2 Summary of significant toxic effects of inorganic
phosphorus compounds 1-7
2-1 United States producers of elemental phosphorus (1988) 2-4
2-2 Estimated emission factors for point source emission of
phosphorus to the environment 2-8
3-1 Distribution and excretion of radioactivity in rats
receiving 32P white phosphorus 3-4
3-2 Lethality of phosphine in animals 3-13
3-3 Oral and subcutaneous toxicity of white phosphorus in
rats 3-19
3-4 White phosphorus/felt smoke induced visceral and skeletal
variations and abnormalities 3-23
3-5 Gross symptoms of patients who ingested elemental
phosphorus 3-29
3-6 Oral toxicity of elemental phosphorus in humans 3-30
3-7 Acute hazard levels of phosphine in humans 3-34
v
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PREFACE
The Office of Health and Environmental Assessment has prepared this
summary 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 Elemental and the selected Inorganic Phosphorus Compounds as hazardous air
pollutants.
In the development of the summary health assessment document, the scien-
tific literature has been inventoried through February 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 concentration-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.
vi
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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.
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 exclu-
sively 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 remobflization from sinks (i.e., soil and aQuatic sediments) nay
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 fn 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 Mg/m3 as a more likely upper limit.
Estimated community exposures as a result of deployment of white and red
phosphorus screening smokes are 146 mg/m* 100 m downwind and 0.963 mg/m
5,000 m downwind (as P20g). Community exposures are transitory and are not
expected to be severe at distances greater than 300 m.
1-1
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Elemental white phosphorus can be absorbed by ingestion, inhalation, and
dermal contact. The major tissues accumulating white phosphorus are liver,
kidney, lung, bone, and skeletal muscle. One inhalation study with radio-
labelled 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 phosphorus deal primarily
with white phosphorus, and to a lesser extent with red phosphorus. Addition-
ally, 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 summarizes significant toxic effects
of elemental phosphorus 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. i>v*rt 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/m in
working'humans and 1,000 vg/m3 in resting humans, but exposure to concentra-
tions 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,
1-2
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TABLE 1-1. SUMMARY Of SIGNIFICANT TOXIC EFFECTS OF ELEMENTAL PHOSPHORUS COMPOUNDS
Lethality
Mutagenicity/
Carcinogenicity
Teratogenicity/
Reproductive Effects
Skin and Eye
Irritation,
Sensitization
Other Effects/
Target Organ
White phosphorus (WP)
White phosphorus/felt saoke
(WF)
LCtso ¦ 94,126 ag'Hln/a3,
rat
LCtso * 5,321
guinea pig
U>uq = 50-100 tag, himns
WP and WP/F not
¦utagenlc In
Salwonella; WP/F
not Mutagenic in
Drosphlla and rats;
no carclnogencity
data found
WP/F not teratogenic
In rats. Repeated
oral doses of 0.75
Mg/kg WP caused high
Mortality in pregnant
rats. NOAEL = 0.015
¦g/kg
HuMans and anlaals:
WP causes severe skin
burns; 0.1 percent WP
in oil not irritating
to rabbit skin and
eyes; WP/F severely
irritating to skin
and eyes of rabbits;
WP/F not sensitizing
Inhalation exposure
HuMans: 700 mg/m3 1s Minium
harassing concentration in
working huMans, 1,000 mg/m3 1n
resting huMans; 185 mg/m3 for
5 Min produces respiratory
distress; chronic exposure May
cause necrosis of the jaw, other
bone abnoinallties, and liver
AnlMals: LOAEL0 = 193 mg/m3
daMage (rats) based on effects
noted 1n the respiratory tract,
changes 1n body and organ
weights, and blood cheMistry and
hematology after subchronlc
exposure; subchronic exposure
to lower levels (160 Mg/M3)
have reportedly produced bone
changes In rats
Oral exposure
HuMans: 15 Mg May cause toxic
syMptoMs; Major target organs
are the gastrointestinal tract,
liver, kidneys, brain, and
cardiovascular systeM; fatty
degeneration of the liver is
a characteristic lesion of
phosphorus poisoning
AnlMals: toxic effects slMllar
to effects seen In hunans; Major
organs affected are t*"> liver,
kidneys, gastrointestinal tract,
and heart; levels of 1.48 g/kg
produced lethargy, gastric
distress, prostration, and death
In Mice, rats, and rabbits;
severe hypoglyceMia, suggestive
of liver daMage, reported in dogs
given 0.5 Mg for several days
(continued on the following page)
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fMLE i-i: tcontinued)
Lethality
Mutagenicity/
Carcinogenicity
Teratogenicity/
Reproductive Effects
Skin and Eye
Irritation,
Sensitization
Other Effects/
Target Organ
Red phosphorus/butyl rubber smoke
LCtso = 222.715 mg-mln/m3,
rat
LCtso = 4,040 ig-iln/i*,
guinea pig
LOtso = >451,680 mg-min/m3,
dog
Nonautagenic in
Salmonella; no
carcinogenicity
data found
No data found
Severe skin and eye
irritation and
corneal ulceration
In rabbits; not
sensitizing in guinea
Pigs
Denial exposure
Nutans: severe burns are associ-
ated with Massive hemolysis,
changes in blood chemistry,
oliguria, and renal failure
Inhalation exposure
Humans: no data found
Animals: respiratory distress,
abnormalities of larynx and
trachea, alveolitis, broncho-
pneumonia, decreased liver, kidney
and body weight, and decreased
pulmonary bactericidal activity.
aN0AEL = No-observed-adverse-effect level.
HoAEL = Lowest-observed-adverse-effect level.
¦c»
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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 intoxi-
cation 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 concentra-
- tion of 150 to 160 mg/m of yellow phosphorus 30 minutes daily for 60 days also
develop the typically widened epiphyseal 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 m1nutes/day for 13 weeks was 40 percent. Histopathological
examination revealed laryngitis, tracheitis, congestion, and bronchitis. A
lowest-observed-adverse-effect-level (L0AEL), based on effects on the respira-
tory 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 time.
Humans occupational1y exposed to white phosphorus nay develop necrosis of the
jawbone, a specific suppurative lesion that can result 1n 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.
1-5
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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 mating, 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 (N0AEL) 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.
Phosphlne (PHg), 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
1-6
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TABLE 1-2. SUMMARY OF SIGNIFICANT TOXIC EFFECTS OF INORGANIC PHOSPHORUS COMPOUNDS
Lethality
Mutagenicity/
Carcinogenicity
Teratogenicity/
Reproductive Effects
Skin and Eye
Irritation,
Sensitization
Other Effects/
Target Organ
Phosphlne (PHS)
LCS0 = 15.4 ag/a3 (4 hr), rat
IDLH* = 280 mg/m3
No data found
No data found
Not Irritating
Phosphorus pentoxlde (P20s)
LCjo ¦ 61 ag/a3 (1 hr),
guinea pig
LCS0 = 271 ag/a3 (1 hr),
douse
LCS0 = 1,212 ag/a3 (1 hr),
rat
LCS0 ¦ 1,689 ag/a3 (1 hr),
rabbit
No data found
No data found
Huaans: skin, eye,
and mucous aeabrance
Irritation; corrosive
Inhalation exposure
Huaans: Inhalation of 14.0 ag/a3
for several hours produces gastro-
intestinal, cardiac/respiratory,
and central nervous systea
syaptoas; long-tern exposure to
0.04 ag/a3 or less causc-s headaches
Aniaals: exposure to nonlethal
levels of phosphlne produce aild
Irritation; aajor target organs
are the respiratory tract, liver,
kidneys, heart, and brain
Oral exposure
Huaans: no data found
Aniaals: Ingestion of phosphine-
treated diets containing
0.996 ag/kg phosphlne for 2 years
produced no treat*ent-related
effects 1n rats
Inhalation exposure
Huaans: 0.8-5.4 ag/a3 tolerated
level, 3.6-11.3 ag/a3 tolerated
with cough; 100 ag/a3 not
tolerated by unaccllaated
individuals
Aniaals: no data found on the
effects on target organs
Oral exposure
No data found on the effects of
Ingestion of phosphorus pentoxlde
In huaans or aniaals
(continued on following page)
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tMllt 1-2. tconttaued)
Lethality
Mutagenicity/
Carcinogenicity
Teratogenicity/
Reproductive Effects
Skin and Eye
Irritation,
Sensitization
Other Effects/
Target Organ
Phosphoric acid (H3PO4)
LDS0 = 1,530 ag/kg (oral), rat
LDso = 2.740 mg/kg (dermal),
rabbits
Phosphorus trichloride (PCI3)
LCS0 = 590 ag/a3 (4 hr), rat
LCso = 283 ag/a3 (4 hr),
guinea pig
IDLH* = 283 ag/a3
No data found
No data found
Nonautagenlc In
Salaonella; no
carcinogenicity
data found
No data found
Phosphorus pentachlorlde (PC1S)
LCS0 = 295 ag/a3, rat No data found
LDS0 = 1,031 ag/a3 (10 aln), aouse
IDLH - 200 ag/a3
No data found
Huaans: skin and eye
irritation
Huaans: severe skin,
eye, and aucous
aeabrane irritation
corrosive
Huaans: skin, eye,
and aucous aeabrane
irritation, corrosive
Inhalation exposure
Huaans: upper respiratory
tract irritation; 1 ag/a3
irritating to unaccliaated
individuals
Anlaals: no data found
Oral exposure
Huaans: aetabollc disorders and
burning sensation In the throat
and gastrointestinal tract
Anlaals: no data found
Inhalation exposure
Huaans: 10-20 ag/a3 causes
respiratory irritation within
2-6 hours; exposure for 1 to
to 2 years, pulaonary eaphyseaa
Anlaals: upper respiratory tract
Irritation; dystrophic changes
1n the kidneys, liver, and
nervous systea
Oral exposure
Huaans: no data found
Anlaals: produces effects on
organs slallar to that seen
in inhalation experiaents
Inhalation exposure
Huaans: respiratory tract
tract Irritation, possible kidney
daaage
Anlaals: respiratory tract
Irritation, kidney, liver,
and nervous systea dystrophy
Oral exposure
Huaans: no data found
Animals: produces effects slallar
to those seen during inhalation
exposure
(continued on following page)
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TABLE 1-2. (continued)
Lethality
Mutagenicity/
Carcinogenicity
Teratogenicity/
Reproductive Effects
Skin and Eye
Irritation,
Sensitization
Other Effects/
Target Organ
Phosphorus oxychloride (P0C13)
LCS0 = 303 mg/m3 (4 hr), rat
IC50 = 335 mg/m* (4 hr),
guinea pig
Chromosomal aber-
rations in rats;
no carcinogenicity
data found
Effect on sperm
Motility in rats
Humans: skin, eye,
and nucous membrane
irritation; corrosive
Phosphorus sesoulsulfide
LDso = 100 mg/kg (oral), dog
No data found
No data found
Humans: allergic
contact dermatitis
and sensitization
Inhalation exposure
Humns: threshold exposure
concentration for Irritation
reported to be 1 mg/m3.
Animals: respiratory tract
Irritation, kidney, liver, and
nervous system dystrophy;
1.34 mg/m* for 4 months causes
respiratory Irritation,
degenerative changes of
brain and bone tissue,
liver and kidney dystrophy
Oral exposure
Humans: no data found
Animals: dystrophic changes 1n
the kidneys, liver, and nervous
system
Inhalation exposure
Humans: prostration, vertigo,
gastrointestinal effects, and
loosening of teeth from long-
term use of matches
Animals: no data found
Oral exposure
No data found on the ingestion
of this compound by either man
of experimental animals
*IDLH = Immediately dangerous to life and health.
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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 LCjq of 15.4 mg/m 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/m ) have been
tolerated for 34 days without clinical injury. Long-term ingestion of a
phosphine-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/m for
several hours fall into three main categories; gastrointestinal (diarrhea,
nausea epiga'stric 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/» 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 (PjOj) avidly absorbs
moisture from the air, forming phosphoric add. Because of its great affinity
for water it is used as a drying agent. Phosphorus pentoxide is the primary
' .. * white or red phosphorus is burned in air. The major
combustion product when wmte pi r v
, ^ is by hydrolysis to phosphoric acid.
environmental transformation is vy 3 , .
locally corrosive and irritating to mucous mem-
Phosphorus pentoxide is iw. r
¦ because of its strong dehydrating action and exothermic
branes, eyes, and sKin oecau*
1-10
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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 1n contact with the eyes cause burns of the eyelids and
cornea.
A leading Inorganic acid in the U. S. economy, phosphoric acid (H^PO^) 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 the
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 LD^q 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/m , 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
hyHrochloric and phosphoric acid. Acute as well as chronic health effects have
been reported In workers exposed to 11 to 23 mg/m 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.
1-11
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Phosphorus pentachloride (PCIg) is very irritating to all mucous surfaces,
including the lungs. The chemical can cause serious skin burns by an exother-
mic reaction with moisture, forming hydrochloric and phosphoric acid. One
report indicated that phosphorus pentachloride may produce kidney damage.
Phosphorus oxychloride (POCl^) 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/m 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 (P3S4) 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 com-
pounds 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.
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2. BACKGROUND INFORMATION
This review provides a brief summary of the available information concern-
ing 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 folubility in water. At room temperature, white phos-
phorus 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, 1s the least known form of phosphorus. It is insoluble in
2-1
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most solvents and thermodynamically the most stable of the phosphorus allo-
types.
Analytical methods for the detection of white phosphorus in air include:
neutron activation analysis (Carlton and Lehman, 1971), flame emission photome-
try (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
Phosphine (PH3) (CAS No. 7803-51-2), a toxic gas with an odor of decaying
fish, ignites spontaneously 1n air in the presence of traces of diphosphane
(^2*^4) anc* 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 al., 1966), and column/paper chroma-
tographic methods (Muthu et al., 1973).
Phosphorus pentoxide, also known as phosphoric anhydride (PgO^) (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 (HjPO^) (CAS No. 7664-38-2)
exists as a clear syrupy liquid or as deliquescent crystals (Heimann, 1983).
It 1s a tribasic acid, stronger than acetic, oxalic, or silicic acid, but
weaker than sulfuric, nitric, hydrochloric, or chromic acid. The most concen-
trated 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).
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Phosphorus trichloride (PC13) (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 trichlo-
ride 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 (PClg) (CAS No. 10026-13-8) is a yellow, fuming,
crystalline mass with a pungent unpleasant odor. It reacts with water, hydro-
lyzing 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
deposition It emits fumes of Cf. P0X, and N0X (Sax, 1984).
Phosphorus sesquisulfide (f>3S4) (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,
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 A9ency, 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 (Lowenhelm and Moran, 1975).
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TABLE 2-1. UNITED STATES PRODUCERS OF ELEMENTAL PHOSPHORUS (1988)
Company
Annual Capacity
(thousands of
Location metric tons)
FMC Corporation Pocatello, ID 137
Monsanto Company Soda Springs, ID 95
Occidental Petroleum Corporation Columbia, TN 57
Stauffer Chemical Company Mount Pleasant, TN 45
Silver Bow, MN 42
Capacity data are on a P4 basis.
Source: SRI International (1988).
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, 1981).
Most of the white phosphorus produced is ultimately utilized in the produc-
tlon of phosphoric acid and phosphates (lowenheim and Moran, 1975). It is also
used in the production of phosphorus sulfides, phosphorus halldes, phosphorus
pentoxide, and red phosphorus. It is used in ferrous metallurgy, in insect
and rodent poisons, and in the manufacture of artificial fertilizers, semicon-
ductors 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 Wa2er, 1982).
There are no current uses for black phosphorus (Hawley, 1981).
2.2.2 Inorganic Phnsphorus Compounds
Phosphine is not considered an Important industrial chemical (Bellies,
1981) Commercially, phosphine 1s produced by the reaction of aluminum phos-
phide with water or by an electrolytic process whereby nascent hydrogen reacts
with elemental phosphorus (Boenig et al., 1982). It is used as a grain
fumlgant as a doping agent for electronic components, in chemical synthesis
(American Conference of Governmental Industrial Hygienists, 1980), and in the
control of rodents and moles by placing the compound in outdoor burrows and
closing the openings (Hayes, 1982).
2-4
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Phosphorus pentoxide Is made commercially by burning phosphorus In a stream
of air. s ma e U. S. production of phosphorus pentoxide in 1985 was 6,300
thousand tons (Toxnet, 1989). Phosphorus pentoxide has a great affinity for
water and is used in this capacity as a drying agent (Beliles. 1981). It is
also used in the nanufacture of phosphorus oxychloride, acrylate esters and
surfactants, as a catalyst in air blowing of asphalt, and in other applications
(Boenig et al., 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, litho-
graving, 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
^3^3) (Boenig et al., 1982). It is used as an intermediate in the prepara-
tion of pesticides, surfactants, gasoline and lubricating oil additives,
plasticizers, and dyes, as a catalyst, and as an ingredient in textile
2-5
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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, particu-
larly 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. The 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 phos-
phate rock. It occurs in all fertile soils and in small quantities in granitr
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 1n 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 coubustion, and
forest fires) (U. S. Environmental Protection Agency, 1982; Mishra and Shukla,
1986; Raison et al., 1985).
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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 \jg/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/m /hour (worst-case upper limit), with a more likely upper limit of
3
0.5 M9/m /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
o 5
146 mg/m (as P20&) 100 m downwind from deployment to 0.963 mg/m , 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 combus-
tion 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 1s 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, concen-
trations of approximately 5,000 parts per million (ppm) were found in the
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TABLE 2-2. ESTIMATEDqEMISSION^ACTORS^FOR^PQInt SOURCE EMISSION OF
Industry or Activity Description
Phosphate rock mining and
beneficiation:
Eastern operations
Western operations
Industrial Manufacturing:
Elemental phosphorus
Dry process phosphoric acid
Phosphorus pentoxide
Phosphorus trichloride
Phosphorus oxychloride
Phosphorus pentasulfide
Sodium phosphate
Feed-grade calcium phosphates
Phosphorus based detergents
Direct acid treatment of metal
surfaces
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 phosphates
Air Emission
(kg P/MT product)
Discharged Waste
Water
(kg P/MT product)
0.094
0.180
0.64
0.57
8.50
10.8
4.74
15.14
2.0
2.4
0.007
0.12
0.166
0.007
0.47
0.35
0.149
2.2
2.6
0.005
0.15
0.044
0.024
0.05
0.05
0.034
0.004
0.17
0.029
0.044
0.0006
0
0.0003
0.00002
0.002
0.33
0.026
Source: U. S. Environmental Protection Agency (1979).
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 a!., 1976). Lai et al. (1979)
reported concentrations of white phosphorus in Yellow Lake, Pine Bluff
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Arsenal, ranging from 0.005 to 0.010 pg/L, while the Arkansas River contained
0.003 to 0.004 |jg/L.
2.3.2 Inorganic Phosphorus Compounds
Exposures to phosphine may occur when add 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
roay 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 m /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 hydra-
tion 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 Hg/year (9.1 tons/year) (U. S.
Environmental Protection Agency, 1980a).
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Phosphoric add Is the »>jor 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.
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 (t.,, = about 5 minutes),
while red phosphorus/butyl rubber was more persistent in lir (t, „ = 1.8 years)
(Spanggord et al., 1985). 1/2
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 phospho-
rus 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.
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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 pentoxide 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 trichlo-
ride, 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 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
2-11
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discharge have ingested lethal quantities of el*ma ~ ,
et al., 1950). In a series of experiments cond Ph°Sphorus (Coburn
ducks there was a marked Individual variation" bl3Ck and mallard
of 3 mg/kg of body weight resulted in death " 10 t0lerance« but * single dose
studied. Acute poisoning caused depression foil ^ 33 h0UrS 1n 311 ducks
convulsions, and death. Birds suffering fr'om °h ^ ^ Weakness» v1°lent
weight and showed signs of paralysis An m C. r°niC pofson1n9 steadily lost
hi i poisoned KiVh ..
degeneration of muscle tissue, liver, and kidne s dlsPlayed fatty
Much of the available information concern^ th
phorus to aquatic species derives from studies i 't' t0X1Clty of whHe Phos"
massive fish kill caused by wastewater discharoedV^ response to a
production plant in Long Harbour, Placentia Ba n ^ ^ ERC° phosphorus
(1972) reported an 80 percent decline in the H°dder et aL
(herring) in Placentia Bay over a 1-month period harenAu?
a decreased yield in nearby St. Mary's Bay, where h •* reSulted also 1n
Massive herring mortalities were observed up to 60^-^ "n9rate to reProduce-
pollution site in Placentia Bay (Zitko et al 1970) mileS fr°m the locall'zed
In static tests with fish, Lepomis macrochirus fblu.n«i
most sensitive species with a 96-hour LC ^7!—// sunfish) was the
(channel catfish) was the least sensit1ve°w1th a **7^
dynamic bioassays, fish were even Bore sensitive to whit. 50„ . '
LC50 for bluegill was 2.4 pg/l and that for channel eatfi k !!' "5' The
et al., 1978). The LT50 for Saivelinus fontinaH, (broo t
0.5 pg/L was 121 hours (Fletcher et al., 1970) 7„h U
(Atlantic salmon) exposed to 0.79 mo/L was 195 hour tc "
1972). incipient levels (lethal concis ion for 5 pe^T ""
long exposure) ranged fro, „ pg/L f0P T'lit
18 MS/t for Atlantic salmon (Zltto .t a,., 1970). Haddock ^ ^ * £
measured the e:ute toxicity of dissolved elemental nh.c„K
/!* f"h°Ur LCs0 ^ M'4 M9/L and the 1"cipient lethaMeveVwas
approximately 1.0 to 2.0 pg/L. The toxic effect u
salmon, and lobster was irreversible and probably cumulativ^^Zitko^et^a"9'
1970). In flow-through studies of critical life stage, Bentley et al (197«
found that the most sensitive life stages for Pimephales pJL (fathead
minnow) are 30-day-old and 60-day-old fry. •
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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 jjg/L was so stunted that internal and exter-
nal 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
etal., 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 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 bi©concentration 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; Haddock 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
nuscle 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
2-13
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decrease in the initial pdmsphorus cmrtemt, but in almost all of the samples,
about 40 percent or more remained.
In chronic studies with macroi'rn»«ntebrates, exposure of water fleas
(Daphnia magna) to 8.7 vg/L of phosptonus significantly reduced survival.
Concentration of <6.9 pg/i did not afjfect survival or the number of young
produced by first and second generations CBentley 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 PelHcu1osa» a diatom, and Seltenastrum 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 diversifty and by selective mortality. Pearson
et al. (1976) reported that phosphorus and phosphate species were significant
factors governing the distribution of toenthic organisms in Yellow Lake, Pine
Bluff Arsenal, Arkansas. Surveys of Wlacentia Bey, Newfoundland, showed that
the only live benthic species collects* in the vicinity of the outfall was
Modiolus modiolus (sea mussel). A more distant location showed reduced biomass
and diversity. Scallop mortalities tene observed 1,000 m from the pipe.
Five percent of a population of sand (dollars (Echinarachnius parma) were
surviving in an area where 90 percent Msuild 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 xnnnpmunds was a study designed to determine
the effect of acidity onfcUuegill stmfffsh. In that study Ellgaard and Gilmore
(1984) exposed bluegill suicfish to /®rfi«us concentrations of phosphoric acid.
No wortality was observed from pH 5-® to 3.5. When the pH reached 3.25 and
3.0, the nortality was 13 and 100 percent, respectively. At sublethal concen-
tration the fcluegill •became hypoactiwe.
2-M
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3. HEALTH EFFECTS
3.1 PHARMACOKINETICS AND METABOLISM
There are only limited quantitative data on the pharmacokinetics and meta-
bolism 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 phosphorus compounds and are discussed elsewhere in this document.
3.1.1 Elemental Phosphorus
Only one study was found on the absorption of inhaled elemental phospho-
rus. 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/m^ ^P-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 diffi-
cult to determine whether the phosphorus was actually absorbed (Oalhamn and
Holma, 1959).
After administering rats 0.75 mg of radiolabeled phosphorus by gastric
intubation, Ghoshal et al. (1971) reported that within 2 to 3 hours follow-
ing 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
32
2 hours. Lee et al. (1975), after administering rats 0.1 percent P-white
phosphorus 1n 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 mjscle.
3-1
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Cameron and Patrick (1966) demonstrated that phosphorus is absorbed after
32
administering 0.5, 3.5, and 20.0 mg of P-white phosphorus to mice, rats, and
rabbits, respectively, by gastric intubation. After 48 hours, the distribution
of radiolabeled phosphorus was fairly uniform across species. The relative
distribution was blood > feces > bowel > liver > kidney > spleen > lung >
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.
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 phos-
phorus 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 pCi/kg of ^P 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 ouiescent areas. This
difference, which was maintained throughout the observation period, was attrib-
32
uted to the greater incorporation of P in nucleic acids 1n 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 1n Section 3.8.1. Hughes et al. (1962) did not find significant
3-2
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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 ^P-white 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 P-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
32
fecal content of P-white phosphorus was 2.0 percent, 16.6 percent, and
33.0 percent at 4 hours, 1 day, and 5 days, respectively. The autho.s did not
determine whether the radioactivity in fecal material was due to direct elimi-
nation from the gastrointestinal tract or was the result of biliary excretion.
32
Thin layer chromatography of the urine from rats administered P-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 metabo-
lites with properties similar to those found in the urine (Lee et al., 1975).
3-3
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TABLE 3-1. DISTRIBUTION AND EXCRETION OF RADIOACTIVITY
IN RATS RECEIVING 32P-WHITE PHOSPHORUS
Percent of Administered Dose
4 Hours 1 Day 5 Days
Gastrointestinal
tract plus contents
57.0
±
3.4C
15.3 ± 4.0
1.7 ± 0.2
Feces
2.0
±
1.0
16.6 ± 3.8
33.0d
Whole blood®
6.1
±
1.1
4.1 ± 0.5
1.7 ± 0.0
Urine
17.1
±
2.2
34.5 ± 6.1
46.7d
Liver
16.1
±
4.6
16.9 ± 0.7
6.3 ± 0.3
Kidneys
0.7
±
0.2
0.8 ± 0.1
0.4 ± 0.0
Spleen
0.1
±
0.0
0.1 ± 0.0
0.1
Brain
0.1
±
0.0
0.1
0.1
Lungs
0.4
±
0.0
0.3 ± 0.1
0.2 ± 0.0
Skeletal muscle'3
4.0
±
0.0
5.5 ± 0.2
6.0 ± 0.6
Recovery
98.6 ± 5.0
94.0 ±3.3
96.0
aBased on 7.0 percent of the body weight.
bBased on 40 percent of the body weight.
cMean ± S.E. of three rats.
dPooled samples from three rats.
Source: Lee et al. (1975).
3.1.2 Inorganic Phosphorus Compounds
The effects of phosphine on numerous organs suggest a wide tissue distri-
bution (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
netabolized to phosphates, thereby simply adding to the pool of existing phos-
phates. 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 an 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
3-4
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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
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 gal late 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
3-5
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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 etal., 1988). These biochemical alterations
were observed following single (1 g/m 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.
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 trans-
port 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 a-ketoglutarate. The coenzyme A levels
in liver mitochondria were slightly lower than 1n controls and the oxidative
phosphorylation of heart, but not of liver mitochondria, was reduced (Neubert
and Hoffmeister, 1960).
3-6
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No information was found In the published literature on the biochemical
effects of phosphorus pentoxlde, phosphoric acid, phosphorus trichloride,
phosphorus pentachloHde, phosphorus oxychlorlde, or phosphorus sesquisulfide.
3.3 ACUTE TOXICITY
3.3.1 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 concentra-
tion x time (C x T) 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 C x T 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 toxicity 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 LCt5£) 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/m died during the 30 minute exposure
period. However, no other deaths or adverse effects were observed in guinea
pigs at C x T values ranging from 545 to 3,840 mg'Hiin/m3. Respiratory distress
was a common problem in animals exposed to C x T 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 C x T values of 14,310
3 3 3
and 48,060 mg«min/m corresponding to 477 mg/m for 30 minutes and 801 mg/m
3-7
-------
for 60 minutes, respectively, died during exposure or within 15 minutes after
exposure, except one animal whith 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).
Manthei et al. (1980) tested white phosphorus/felt smoke for inhalation
toxicity in rats. Exposure to a concentration of 1,400 mg/m3 for 1 hour
produced immediate toxic effects consisting of dyspnea and prostration lasting
up to 24 hours. The 14-day mortality was 70 percent.
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/m3, respectively. Mortality ranged from 5
percent at 110 mg/m3 to 95 percent at 1,690 ng/n3 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 mani-
festations 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 1n seven animals, significantly 1n six. The severe hypoglycemia
suggested that the liver was damaged.
Cutler (1931) obtained similar results «rfth 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.
3-8
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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.
Manthei et al. (1980) also administered white phosphorus/felt residue to
rats at doses of 5.0 mL/kg or 0.05 mL/kg (volume based on the undiluted residue)
by gastric intubation. All animals given 5.0 mL/kg died within 24 hours,
whereas animals administered 0.05 mL/kg displayed no signs of toxicity.
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 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
3-9
-------
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 abnormal-
ities (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/m 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
3
ranging from 0.5 to 3 g/m for 1 to 4 hours showed highly significant decreases
In pulmonary bactericidal activity to inhaled radiolabeled Klebsiella
pneumoniae 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.
3-10
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Subsequent mortality studies with red phosphorus/butyl rubber aerosols
suggest that exposure concentration Is the determining factor in mortality
Tn , IT " °f eXp0sure- Rat,s «re 9iven single 1-hour exposures of
' ' ' 3'09, or 315 3/m ,nd observed for 14 days. Maximum
¦ortality (20 to 25 percent) occurred after a 1-hour exposure to 3 g/m3, while
i+K 9 r r"ulted 6 Pef*cent deaths. A single 4-hour exposure to 0.88 g/m3
with a x T 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/m red phosphorus/butyl rubber smoke aerosols for 1 hour or to
1.5 g/m 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 cyclo-
polyphosphoric 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/m for 1 hour, one animal died on day 6 and 10 postexposure. Exposure to
1.5 g/m 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/m 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/m 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.
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3.3.2 Inorganic Phosphorus Compounds
Symptoms observed in rats, resulting from single acute inhalation
exposures to phosphine, were typical of mild irritation, such as red ears,
salivation, lacrimation, face pawing, and dyspnea. Histologic examination of
tissues did not show any pathologic changes. The 4-hour LC5Q was 15.4 mg/m .
Repeated 4-hour inhalation exposures to about 5.6 mg/m^ for 10 days produced
mild respiratory irritation 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/m (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
3
fatal concentration (7.5 mg/m ) 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
3
7.5 mg/m phosphine and above, the effects were cumulative, while concentra-
3
tions of 3.75 mg/m and below produced no clinical evidence of cumulative
effects (rats tolerated 3.75 mg/m 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
pronojnced dilatation of the perivascular spaces, changes in the nuclei of
ganglion cells with glial reaction, disintegrating Purklnje cells with multi-
plication of the Bergmann glla, 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.
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TABLE 3-2. LETHALITY OF PH0SPHINE IN ANIMALS
Species
Route
Concentrati on/Effect
Rat
Inhalation
16.5 mg/m3 4 hr, LC50
Mouse
Inhalation
412.5 mg/m3 2 hr, LCLo
Guinea pig
Inhalation
150.0 mg/m3 2 hr, LCLq
Rabbit
Inhalation
3,750.0 mg/m3 20 min, LC^Q
Cat
Inhalation
75.0 mg/m3 2 hr, LC,Q
Source: RTECS 1989.
Acute toxicity data for phosphorus pentoxide in laboratory animals
indicate a wide interspecies difference. The acute 1-hour inhalation toxicity
of phosphorus pentoxide in terms of LCgg 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 LD5Q value of 1,530 mg/kg for rats and a dermal LD^q 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 (HjPO^) 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 (HPO^) 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/m 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
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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 only
slightly reduced in rats, but significantly reduced in guinea pigs.
Russian investigators (Roshchin and Holodkina, 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^m or about 40 PPm) and !ess toxic by the oral route
(LD5o = 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 LC5Q for rats is 295 mg/m3.
The oral LD5Q 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 LCg0 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 1n the vapor phase, was not significantly affected by neutralization
with ammonia.
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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 LCgg was 71 mg/m^ (exposure time not given).
An oral LD^q value of 100 mg/kg in dogs was the only information found
for effects of phosphorus sesquisulfide in experiment!a 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/m^ yellow
phosphorus 30 minutes/day for 60 days developed bone changes consisting 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 concentra-
3 3 3
tions were 1,161 mg/m (high), 589 mg/m (intermediate), 193 mg/m (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.
3-15
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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, hyper-
keratosis 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).
Strelyukhlna (1984) reported hepatic changes in rats in the form of
congestion, fatty degeneration of the hepatocytrs, and toxic hepatitis after
orally ingesting 1.0 »g/kg of white phosphorus for 15 days to 4 months.
Fibrosis and internodular cirrhosis was evident 1n some animals exposed to
phosphorus for 3 to 4 months. Similar results were reported by Mallory (1933)
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
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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 distrib-
uted 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 1n 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
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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 trabeculae due to reduced resorp-
tion 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
t
mortality rate was lower than that 1n controls. Thus, as In the oral study,
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TABLE 3-3. ORAL AND SUBCUTANEOUS TOXICITY OF WHITE PHOSPHORUS IN RATS
Dose
(mg/kg/day)
Total Dose
(mg)
Average Survival
(days)
Deaths/100
Animal-Days
Oral
Controls
1.6
0.8
0.4
0.2
718
265
181
96
0
449
332
454
479
348
0.25
0.30
0.22
0.21
0.33
Subcutaneous
Controls
3.2
1.6
1.2
0.8
0.4
0.2
0.1
0.05
10
15
13
112
136
89
53
31
0
11
140
340
442
530
610
480
3.2
0.3
31.6
10.7
9.1
0.72
0.30
0.23
0.19
0.17
0.24
Source: Fleming et al. (1942).
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
3-19
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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
Col lings (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.
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. Con-
centrations 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.
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
3-20
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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/m , 4 hours/day, for 2 months, but died after seven similar exposures to
14 mg/m3. After repeated exposures to 14 mg/m3, 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.
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
Phostox1n®-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
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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).
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 minute (starting on day 6 of pregnancy and continuing
to day 15) to concentrations of 0, 500, or 1,000 mg/m3 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/m white phosphorus/felt
smoke to evaluate the affect 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/m .
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TABLE 3-4. WHITE PHOSPHORUS/FELT SMOKE INDUCED VISCERAL AND SKELETAL
VARIATIONS AND ABNORMALITIES
Variations Air Low Dose High Dose
and Abnormalities Control 500 mg/m3 1,000 mg/m3
Visceral
Prominent renal pelvis 4 3 5
Ectopic kidney(s) 1 4
Narrow attrium 111
Thin-walled heart 1
Reversed ductus arteriosus 9
Underdeveloped testicles 3 l
Ectopic testicles 3
Hemorrhagic eyes * 1
Anophthalmia* unilateral
Short tongue * 11
Brachygnathia 1
Skeletal
Fourteenth rib extra 16 39 25
(rudimentary)
Cleft sternebrai 2 0 2
Dumbbell-shaped sternebrae 16 7 6
General hypoplasia of the 35 46 38
sternebrae
Dumbbell-shaped 9 11 2
vertebra - thoracic
Hypoplasia of xyphoid 2 11 19
process
Abnormalities.
Source: Starke et al. (1982).
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) phospho-
rus was administered by flavage 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
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effects of yellow phosphorus in exposed males, females, or pups. A "no-
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 pL/plate produced no mutagenic activity in Salmonella
typhimuriurn strains TA100, TA1535, TA98, TA1537, and TA1538 either in the
presence or absence of metabolic activation (Ellis et al., 1978). A negative
response in these strains was also obtained by Manthei et al. (1980) using
white phosphorus/felt smoke residue at concentrations of 0.001 to 10.0 pL/plate.
A concentration of 10 pL/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
Saccharomvces cerevisiae exposed to red phosphorus (McGregor, 1980).
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.r 1980)
Starke et al. (1982) conducted studies to determine if white phosphorus/
J i —~ lethal mutations in rats. Fertile male rats were
felt smoke produced dominant lethal mutations
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exposed for 15 minutes/day, 5 days/week for 10 weeks to smoke concentrations of
0, 500, or 1,000 mg/m3. The rats were mated during the first and second week
after exposure. Four animals died during exposure to the highest concentra-
tion. 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 with 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/m ; 0.08 ppm), the chromosomal
aberrations did not differ significantly from those observed in controls.
3.7 CARCINOGENICITY
3.7.1 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 phosphlne via feed. Phosphine was found not to be carcino-
genic 1n rats under the conditions of the studies. Refer to Section 3.4.2 for
details of the studies.
3-25
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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
3 3
concentrations ranged from 185 mg/m to 592 rog/m 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 concen-
tration at which humans may be exposed for 15 minutes without encountering
serious effects.
Walker et al. (1947) reported the effects of inhalation of white phospho-
rus 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 and expectoration subsided within several days but hoarseness
persisted long after other evidence of respiratory tract irritation
disappeared. 3
Five males were exposed to white phosphorus vapors composed of 35 mg/m of
phosphorus and 22 mg/m3 of phosphorus pentoxide at an industrial site
3-26
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(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.
According to Sollmann (1957) the estimated minimal lethal dose of elemen-
tal (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 as 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;
3-27
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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 3-5 summarizes 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 poison-
ing. 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 (Dv/yer 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 abnormal-
ities 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.
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 0.7< 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
3-28
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TABU 3-5. GROSS SYMPTOMS OF PATIENTS WHO INGESTED ELEMENTAL PHOSPHORUS
Age
Sex
Approximate
Dose of
P (B)
Vorftlng
and/or
Heaateaiesls
Abdominal
Pain
CHS
Toxicity
Shock
or low
BP
Hver
Toxicity
Renal
Toxicity
Cardiac
Damage
Other
Effects
tine of
Death or
Recovery
References
Died
65 yr
F
0.10a
-
~
~
+
-
~
-
*
52 hr
LaDue et al., 1944
19 yr
F
0.156
~
~
+
-
~
+
-
-
3% days
Hann and Veale, 1910
31 yrb
F
0.19
+
~
~
~
+
~
-
-
8 days
D1az-R1vera et al., 1950
19 yr
F
0.23
~
-
+
+
-
-
~
-
8 hr
Rubltsky and Myerson, 1949
69 yr
F
0.70
~
-
+
~
~
~
~
-
5 days
McCarron et al., 1981
16 yr
F
1.10
-
-
-
~
-
~
+
Vascular
damge
22 hr
Taltey et al., 1972
43 yr
M
1.134
~
~
~
-
+
~
+
-
Day 5
Caaeron and Rentoul, 1963
28 yr
N
1.57
~
~
+
-
~
-
Hyperphos-
phateala
Day 6
D1az-R1vera et al., 1950
Recovered
10 MS
F
0.12
-
-
~
~
~
-
-
-
Day 5
McCarron et al., 1981
23 yr
F
0.13
~
+
+
-
+
+
-
Leukocytosis
Day 29
McCarron et al., 1981
71 yr
F
0.5
~
-
~
~
~
-
-
Aneala
Day 42
Caley and Kellock, 1955
22 yr
M
0.78
-
~
~
-
~
~
~
Hyperphos-
phatemia
Day 30
D1az-R1vera et al., 1950
30 yr
M
0.78*
+
+
~
+
~
~
4
Aneala
Day 30
Pletras et al., 1968
61 yr
M
1.20*
~
•f
-
-
+
~
-
-
Day 56
LaDue et al., 1944
24 yr
N
1.57
~
~
~
-
+
+
-
-
Day 21
Diaz-Rivera et al., 1950
aDose estimated by McCarron et al., 1981.
^Patient refused Medical treatment.
-------
TABLE 3-6. ORAL TOXICITY OF ELEMENTAL PHOSPHORUS IN HUMANS
Dose (9) No. Cases Mortality (%)
6.30 1 100
4.62 1 100
1.57 21 90
0.78 18 16.3
0.39fa* 14 14.3
0.19 1 100
A
Patient refused medical treatment.
Source: Diaz-Rivera et al. (1950).
16-year-old female who ingested 1.11 g of phosphorus and died within 33 hours
(Talley et al.f 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 (0'Donoghue, 1985).
Because white phosphorus ignites spontaneously in air, it causes severe
burns if it comes in contact with the skin. Phosphorus burns have been sus-
tained 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.
3-30
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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 etal., 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.
Summer!in 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 hemoglo-
binemia, 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 diseasfe 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), Helmann (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 1n 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) «f phosphorus necrosis were discovered; the
majority were women and children less than 16 years old. In three fireworks
3-31
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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 roost disfiguring of all occupational diseases
1n 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 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, 2S38). Also, the delayed onset
of phosphorus necrosis after workers are removed from the source of exposure,
1s 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
3-32
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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 expo-
sure 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/m (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 fro™ ferrous alloys
stored on freight boats, 1n occupants of apartments near fumigated grain
elevators 1n welders breathing acetylene fro* portable generators, and in
3-33
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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 the
presence of dangerous amounts (Heimann, 1983). The acute hazard levels of
phosphine in humans are summarized in Table 3-7.
TABLE 3-7. ACUTE HAZARD LEVELS OF PHOSPHINE IN HUMANS
Concentration
Exposure
Period
Data
1.4 mg/m3
7 hr lx/week
Maximum safe exposure
35 mg/m3
1 hr lx/week
Maximum safe exposure
70 mg/m3
0.1 hr lx/week
Maximum safe exposure
9.8 mg/m3
Several hr
Maximum tolerated
concentration
280 mg/m3
—
Immediately dangerous to
life and health (IDLH)
2,800 mg/m3
Few min
Lethal
Source: Sax (1986).
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, bilirublnuria, 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
3-34
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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
3 3
value of 0.42 mg/m or the odor threshold of 2.0 to 4.0 mg/m . Phosphine
levels in representative areas of the ship were: 28.0 to 42.0 mg/m3 in a void
3 3
space on the main deck, 11.0 to 14.0 mg/m near a hatch, and 0.7 mg/m in some
living quarters.
Jones et al. (1964) reported that most of 67 grain fumigators, intermit-
tently 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 immedi-
ately, 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
L eacultina from grain fumigation in India. Twenty-two
exposure to phosphine resulting Trom « »
workers 4S years, mean duration of exposure 11.1 years) were
examined The phosphine concentration in the work env,ronment ranged from
0.23 to'a.81 -U3. Exposure to the chemical caused mild to moderate
3-35
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respiratory, neurological, and gastrointestinal symptoms which were
transient. They 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 acetylene operator from pulmonary edema. The probable cause of death was
exposure to phosphine at levels of about 11.0 mg/m^ 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- /acuolar 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
etal., 1966), but no such cases have been documented in the available
literature
Phosphoric add My cause irritation of the upper respiratory tract, eyes,
and skin; 1t also My produce sMn burns and de™at1tis CSUtlg, 1985). At a
3-36
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3
concentration of 1.0 mg/m , the Federal standard, phosphoric acid mist is
irritating to unacclimated workers but is easily tolerated by acclimated
workers (Sittig, 1985). The World Health Organization (1986) indicates that
about 0.5 mg/m^ 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 inflam-
matory 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 aid. 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 « well « vapor form 1s highly
Irritating to the skin and oucous membranes, respiratory tract, and eyes.
Severe acid burns car occur (Srant, 1974; Bellies, 1381).
Occupational exposure to phosphorus trichloride during its .anufacture
resulted in acute and subacute adverse health effects In workers who had been
exposed to the chemical fro. 1951 to 1952
-------
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. Pulmo-
nary function tests revealed statistically significant decreases in vital
capacity, maximal breathing capacity, forced expiratory volume in one second,
and 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
et al., 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
3-38
-------
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
3
are similar, namely about 10.0 mg/m. Based on these findings, they suggested
3
a highest permissible concentration in the work place of 0.2 mg/m , 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 oxychloride are
similar in humans and rats. However, phosphorus oxychloride is more irritating,
3
with a threshold exposure concentration of 1 mg/m .
3-39
-------
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 Ryc-oft, 1983).
Intense itching with scaly patches 1n 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
3-40
-------
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 oxychloride, and
phosphorus sesquisulfide). Therefore, these compounds as classified as Group D
carcinogens, not classified as to human carcinogenicity.
3-41
-------
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